Oxidative Stress and Erectile Dysfunction: Pathophysiology, Impacts, and Potential Treatments
Abstract
:1. Introduction
2. Methods
2.1. Literature Search Strategy
2.2. Inclusion and Exclusion Criteria
2.2.1. Inclusion Criteria
- -
- Peer-reviewed articles published between 2000 and 2024.
- -
- Studies focusing on the pathophysiology of erectile dysfunction.
- -
- Research discussing the impact of oxidative stress on erectile function.
- -
- Articles addressing potential treatments for erectile dysfunction related to oxidative stress.
- -
- Reviews, clinical trials, and meta-analyses related to oxidative stress and erectile dysfunction.
2.2.2. Exclusion Criteria
- -
- Non-English publications.
- -
- Studies not focusing on the relationship between oxidative stress and erectile dysfunction.
- -
- Articles lacking full-text access.
- -
- Publications before 2000, unless they provide foundational knowledge.
2.3. Data Extraction and Synthesis
2.4. Quality Assessment and Limitations
3. Mechanisms of Penile Erection and Erectile Dysfunction
3.1. Physiology of Penile Erection
3.1.1. Vascular and Neural Interactions
3.1.2. The Crucial Role of Nitric Oxide (NO)
3.1.3. Contractile Mechanisms in the Penis
3.2. Pathophysiology of Erectile Dysfunction
3.2.1. Vascular-Related ED
3.2.2. Neural-Related ED
4. Role of Oxidative Stress in Erectile Dysfunction
4.1. Oxidative Stress and ROS
4.1.1. Definition and Impact of OS and ROS
4.1.2. Cellular Sources of ROS
NADPH Oxidase (Nox) Family
Xanthine Oxidase
eNOS Uncoupling
Mitochondrial Electron Transport
4.2. Impact of Oxidative Stress on ED
4.3. Influencing Factors and Their Molecular Mechanisms
4.3.1. Aging
4.3.2. Chronic Health Conditions
Diabetes Mellitus
Hypertension
Hyperlipidemia
Chronic Kidney Disease (CKD)
4.3.3. Lifestyle and Behavioral Factors
Smoking
Obesity
Alcohol Consumption
Psychological Stress
4.3.4. Genetic Disorders
Hyperhomocysteinemia
Sickle Cell Disease
5. Antioxidants and Therapeutic Strategies for Erectile Dysfunction
5.1. Endogenous Antioxidants in Penile Health
5.2. Therapeutic Strategies to Mitigate Penile Oxidative Stress
5.2.1. Role of Antioxidants in Penile Oxidative Stress Reduction
5.2.2. Targeting NADPH Oxidase in Penile Tissue
PDE5 Inhibitors and Their Mechanisms
Angiotensin-Converting Enzyme Inhibitors and AT1 Receptor Blockers
Statins and Their Effects on Penile Oxidative Stress
5.2.3. Targeting eNOS Uncoupling to Improve Penile Function
5.2.4. Natural Antioxidant Beverages and Erectile Function Enhancement
6. Future Directions in Erectile Dysfunction Research
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Elterman, D.S.; Bhattacharyya, S.K.; Mafilios, M.; Woodward, E.; Nitschelm, K.; Burnett, A.L. The Quality of Life and Economic Burden of Erectile Dysfunction. Res. Rep. Urol. 2021, 13, 79–86. [Google Scholar] [CrossRef] [PubMed]
- McMahon, C.G. Current diagnosis and management of erectile dysfunction. Med. J. Aust. 2019, 210, 469–476. [Google Scholar] [CrossRef]
- Irwin, G.M. Erectile Dysfunction. Prim. Care 2019, 46, 249–255. [Google Scholar] [CrossRef] [PubMed]
- Sangiorgi, G.; Cereda, A.; Benedetto, D.; Bonanni, M.; Chiricolo, G.; Cota, L.; Martuscelli, E.; Greco, F. Anatomy, Pathophysiology, Molecular Mechanisms, and Clinical Management of Erectile Dysfunction in Patients Affected by Coronary Artery Disease: A Review. Biomedicines 2021, 9, 432. [Google Scholar] [CrossRef] [PubMed]
- Ibrahim, A.; Ali, M.; Kiernan, T.J.; Stack, A.G. Erectile Dysfunction and Ischaemic Heart Disease. Eur. Cardiol. Rev. 2018, 13, 98–103. [Google Scholar] [CrossRef] [PubMed]
- Thomas, C.; Konstantinidis, C. Neurogenic Erectile Dysfunction. Where Do We Stand? Medicines 2021, 8, 3. [Google Scholar] [CrossRef] [PubMed]
- Roychoudhury, S.; Chakraborty, S.; Choudhury, A.P.; Das, A.; Jha, N.K.; Slama, P.; Nath, M.; Massanyi, P.; Ruokolainen, J.; Kesari, K.K. Environmental Factors-Induced Oxidative Stress: Hormonal and Molecular Pathway Disruptions in Hypogonadism and Erectile Dysfunction. Antioxidants 2021, 10, 837. [Google Scholar] [CrossRef] [PubMed]
- Chen, M.; Zhang, Z.; Zhou, R.; Li, B.; Jiang, J.; Shi, B. The relationship between oxidative balance score and erectile dysfunction in the U.S. male adult population. Sci. Rep. 2024, 14, 10746. [Google Scholar] [CrossRef] [PubMed]
- Chirindoth, S.S.; Cancarevic, I. Role of Hydrogen Sulfide in the Treatment of Fibrosis. Cureus 2021, 13, e18088. [Google Scholar] [CrossRef]
- Santos, R.A.S.; Sampaio, W.O.; Alzamora, A.C.; Motta-Santos, D.; Alenina, N.; Bader, M.; Campagnole-Santos, M.J. The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7). Physiol. Rev. 2018, 98, 505–553. [Google Scholar] [CrossRef]
- MacDonald, S.M.; Burnett, A.L. Physiology of Erection and Pathophysiology of Erectile Dysfunction. Urol. Clin. N. Am. 2021, 48, 513–525. [Google Scholar] [CrossRef] [PubMed]
- Andersson, K.E. Autonomic Regulation of Penile Erection; Oxford Research Encyclopedia of Neuroscience: Oxford, UK, 2019. [Google Scholar]
- Mitidieri, E.; Cirino, G.; d’Emmanuele di Villa Bianca, R.; Sorrentino, R. Pharmacology and perspectives in erectile dysfunction in man. Pharmacol. Ther. 2020, 208, 107493. [Google Scholar] [CrossRef] [PubMed]
- Melis, M.R.; Argiolas, A. Erectile Function and Sexual Behavior: A Review of the Role of Nitric Oxide in the Central Nervous System. Biomolecules 2021, 11, 1866. [Google Scholar] [CrossRef] [PubMed]
- Fujimoto, K.; Hashimoto, D.; Kashimada, K.; Kumegawa, S.; Ueda, Y.; Hyuga, T.; Hirashima, T.; Inoue, N.; Suzuki, K.; Hara, I.; et al. A visualization system for erectile vascular dynamics. Front. Cell Dev. Biol. 2022, 10, 1000342. [Google Scholar] [CrossRef] [PubMed]
- Hashimoto, D.; Hirashima, T.; Yamamura, H.; Kataoka, T.; Fujimoto, K.; Hyuga, T.; Yoshiki, A.; Kimura, K.; Kuroki, S.; Tachibana, M.; et al. Dynamic erectile responses of a novel penile organ model utilizing TPEM†. Biol. Reprod. 2021, 104, 875–886. [Google Scholar] [CrossRef] [PubMed]
- Burnett, A.L. The Science and Practice of Erection Physiology: Story of a Revolutionary Gaseous Molecule. Trans. Am. Clin. Climatol. Assoc. 2019, 130, 51–59. [Google Scholar]
- Cripps, S.M.; Mattiske, D.M.; Pask, A.J. Erectile Dysfunction in Men on the Rise: Is There a Link with Endocrine Disrupting Chemicals? Sex. Dev. 2021, 15, 187–212. [Google Scholar] [CrossRef] [PubMed]
- de Souza, I.L.L.; Ferreira, E.D.S.; Vasconcelos, L.H.C.; Cavalcante, F.d.A.; da Silva, B.A. Erectile Dysfunction: Key Role of Cavernous Smooth Muscle Cells. Front. Pharmacol. 2022, 13, 895044. [Google Scholar] [CrossRef] [PubMed]
- Song, S.; Babicheva, A.; Zhao, T.; Ayon, R.J.; Rodriguez, M.; Rahimi, S.; Balistrieri, F.; Harrington, A.; Shyy, J.Y.-J.; Thistlethwaite, P.A.; et al. Notch enhances Ca2+ entry by activating calcium-sensing receptors and inhibiting voltage-gated K+ channels. Am. J. Physiol. Cell Physiol. 2020, 318, C954–C968. [Google Scholar] [CrossRef]
- Ahmed, W.S.; Geethakumari, A.M.; Biswas, K.H. Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors. Biomed. Pharmacother. 2021, 134, 111128. [Google Scholar] [CrossRef]
- Pereira, P.D.S.; Pereira, D.A.; Calmasini, F.B.; Reis, L.O.; Brinkman, N.; Burnett, A.L.; Costa, F.F.; Silva, F.H. Haptoglobin treatment contributes to regulating nitric oxide signal and reduces oxidative stress in the penis: A preventive treatment for priapism in sickle cell disease. Front. Physiol. 2022, 13, 961534. [Google Scholar] [CrossRef]
- Saenz de Tejada, I.; Angulo, J.; Cellek, S.; Gonzalez-Cadavid, N.; Heaton, J.; Pickard, R.; Simonsen, U. Physiology of erectile function. J. Sex. Med. 2004, 1, 254–265. [Google Scholar] [CrossRef] [PubMed]
- Andersson, K.E. Neurophysiology/pharmacology of erection. Int. J. Impot. Res. 2001, 13 (Suppl. S3), S8–S17. [Google Scholar] [CrossRef] [PubMed]
- Panchatsharam, P.K.; Durland, J.; Zito, P.M. Physiology, Erection; StatPearls: Treasure Island, FL, USA, 2024. [Google Scholar]
- Shindel, A.W.; Lue, T.F. Medical and Surgical Therapy of Erectile Dysfunction; Feingold, K.R., Anawalt, B., Blackman, M.R., Boyce, A., Chrousos, G., Corpas, E., de Herder, W.W., Dhatariya, K., Dungan, K., Hofland, J., et al., Eds.; Endotext: South Dartmouth, MA, USA, 2000. [Google Scholar]
- Aydinoglu, F.; Adibelli, E.O.; Yilmaz-Oral, D.; Ogulener, N. Involvement of RhoA/Rho-kinase in l-cysteine/H2S pathway-induced inhibition of agonist-mediated corpus cavernosal smooth muscle contraction. Nitric Oxide 2019, 85, 54–60. [Google Scholar] [CrossRef] [PubMed]
- Wang, H.; Eto, M.; Steers, W.D.; Somlyo, A.P.; Somlyo, A.V. RhoA-mediated Ca2+ sensitization in erectile function. J. Biol. Chem. 2002, 277, 30614–30621. [Google Scholar] [CrossRef] [PubMed]
- Angulo, J.; Cuevas, P.; La Fuente, J.M.; Pomerol, J.M.; Ruiz-Castane, E.; Puigvert, A.; Gabancho, S.; Fernandez, A.; Ney, P.; Saenz De Tejada, I. Regulation of human penile smooth muscle tone by prostanoid receptors. Br. J. Pharmacol. 2002, 136, 23–30. [Google Scholar] [CrossRef] [PubMed]
- Gabani, M.; Liu, J.; Ait-Aissa, K.; Koval, O.; Kim, Y.R.; Castaneda, D.; Vikram, A.; Jacobs, J.S.; Grumbach, I.; Trebak, M.; et al. MiR-204 regulates type 1 IP3R to control vascular smooth muscle cell contractility and blood pressure. Cell Calcium 2019, 80, 18–24. [Google Scholar] [CrossRef] [PubMed]
- Angulo, J.; Cuevas, P.; Fernandez, A.; Allona, A.; Moncada, I.; Martin-Morales, A.; La Fuente, J.M.; de Tejada, I.S. Enhanced thromboxane receptor-mediated responses and impaired endothelium-dependent relaxation in human corpus cavernosum from diabetic impotent men: Role of protein kinase C activity. J. Pharmacol. Exp. Ther. 2006, 319, 783–789. [Google Scholar] [CrossRef] [PubMed]
- McCabe, M.P.; Sharlip, I.D.; Atalla, E.; Balon, R.; Fisher, A.D.; Laumann, E.; Lee, S.W.; Lewis, R.; Segraves, R.T. Definitions of Sexual Dysfunctions in Women and Men: A Consensus Statement From the Fourth International Consultation on Sexual Medicine 2015. J. Sex. Med. 2016, 13, 135–143. [Google Scholar] [CrossRef]
- Kessler, A.; Sollie, S.; Challacombe, B.; Briggs, K.; Van Hemelrijck, M. The global prevalence of erectile dysfunction: A review. BJU Int. 2019, 124, 587–599. [Google Scholar] [CrossRef]
- Corona, G.; Lee, D.M.; Forti, G.; O’Connor, D.B.; Maggi, M.; O’Neill, T.W.; Pendleton, N.; Bartfai, G.; Boonen, S.; Casanueva, F.F.; et al. Age-related changes in general and sexual health in middle-aged and older men: Results from the European Male Ageing Study (EMAS). J. Sex. Med. 2010, 7, 1362–1380. [Google Scholar] [CrossRef] [PubMed]
- Ayta, I.A.; McKinlay, J.B.; Krane, R.J. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int. 1999, 84, 50–56. [Google Scholar] [CrossRef] [PubMed]
- Molina-Vega, M.; Asenjo-Plaza, M.; Banderas-Donaire, M.J.; Hernandez-Ollero, M.D.; Rodriguez-Moreno, S.; Alvarez-Millan, J.J.; Cabezas-Sanchez, P.; Cardona-Diaz, F.; Alcaide-Torres, J.; Garrido-Sanchez, L.; et al. Prevalence of and risk factors for erectile dysfunction in young nondiabetic obese men: Results from a regional study. Asian J. Androl. 2020, 22, 372–378. [Google Scholar] [CrossRef] [PubMed]
- Cyr, A.R.; Huckaby, L.V.; Shiva, S.S.; Zuckerbraun, B.S. Nitric Oxide and Endothelial Dysfunction. Crit. Care Clin. 2020, 36, 307–321. [Google Scholar] [CrossRef] [PubMed]
- Krzastek, S.C.; Bopp, J.; Smith, R.P.; Kovac, J.R. Recent advances in the understanding and management of erectile dysfunction. F1000Research 2019, 8, 102. [Google Scholar] [CrossRef]
- Scioli, M.G.; Storti, G.; D’Amico, F.; Rodriguez Guzman, R.; Centofanti, F.; Doldo, E.; Cespedes Miranda, E.M.; Orlandi, A. Oxidative Stress and New Pathogenetic Mechanisms in Endothelial Dysfunction: Potential Diagnostic Biomarkers and Therapeutic Targets. J. Clin. Med. 2020, 9, 1995. [Google Scholar] [CrossRef] [PubMed]
- Das, D.; Shruthi, N.R.; Banerjee, A.; Jothimani, G.; Duttaroy, A.K.; Pathak, S. Endothelial dysfunction, platelet hyperactivity, hypertension, and the metabolic syndrome: Molecular insights and combating strategies. Front. Nutr. 2023, 10, 1221438. [Google Scholar] [CrossRef]
- Chung, E. Contemporary and Novel Imaging Studies for the Evaluation of Erectile Dysfunction. Med. Sci. 2019, 7, 87. [Google Scholar] [CrossRef]
- Zhang, Y.; Huo, W.; Wen, Y.; Li, H. Silencing Nogo-B receptor inhibits penile corpus cavernosum vascular smooth muscle cell apoptosis of rats with diabetic erectile dysfunction by down-regulating ICAM-1. PLoS ONE 2019, 14, e0220715. [Google Scholar] [CrossRef]
- Doumas, M.; Tsakiris, A.; Douma, S.; Grigorakis, A.; Papadopoulos, A.; Hounta, A.; Tsiodras, S.; Dimitriou, D.; Giamarellou, H. Factors affecting the increased prevalence of erectile dysfunction in Greek hypertensive compared with normotensive subjects. J. Androl. 2006, 27, 469–477. [Google Scholar] [CrossRef]
- Schieber, M.; Chandel, N.S. ROS function in redox signaling and oxidative stress. Curr. Biol. 2014, 24, R453–R462. [Google Scholar] [CrossRef] [PubMed]
- Thomas, S.R.; Witting, P.K.; Drummond, G.R. Redox control of endothelial function and dysfunction: Molecular mechanisms and therapeutic opportunities. Antioxid. Redox Signal. 2008, 10, 1713–1765. [Google Scholar] [CrossRef] [PubMed]
- Ma, Z.; Wang, W.; Pan, C.; Fan, C.; Li, Y.; Wang, W.; Lan, T.; Gong, F.; Zhao, C.; Zhao, Z.; et al. N-acetylcysteine improves diabetic associated erectile dysfunction in streptozotocin-induced diabetic mice by inhibiting oxidative stress. J. Cell. Mol. Med. 2022, 26, 3527–3537. [Google Scholar] [CrossRef] [PubMed]
- Taskiran, M.; Dogan, K. The efficacy of systemic inflammatory response and oxidative stress in erectile dysfunction through multi-inflammatory index: A prospective cross-sectional analysis. J. Sex. Med. 2023, 20, 591–596. [Google Scholar] [CrossRef] [PubMed]
- Mironczuk-Chodakowska, I.; Witkowska, A.M.; Zujko, M.E. Endogenous non-enzymatic antioxidants in the human body. Adv. Med. Sci. 2018, 63, 68–78. [Google Scholar] [CrossRef] [PubMed]
- Tabrez, S.; Ahmad, M. Some enzymatic/nonenzymatic antioxidants as potential stress biomarkers of trichloroethylene, heavy metal mixture, and ethyl alcohol in rat tissues. Environ. Toxicol. 2011, 26, 207–216. [Google Scholar] [CrossRef] [PubMed]
- Hamamcioglu, A.C. The Role of Oxidative Stress and Antioxidants in Diabetes Mellitus. Turk. J. Diabetes Obes. 2017, 1, 7–13. [Google Scholar]
- Cervantes Gracia, K.; Llanas-Cornejo, D.; Husi, H. CVD and Oxidative Stress. J. Clin. Med. 2017, 6, 22. [Google Scholar] [CrossRef] [PubMed]
- Forstermann, U.; Xia, N.; Li, H. Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis. Circ. Res. 2017, 120, 713–735. [Google Scholar] [CrossRef]
- Holmstrom, K.M.; Finkel, T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat. Rev. Mol. Cell Biol. 2014, 15, 411–421. [Google Scholar] [CrossRef]
- Duan, J.; Gao, S.; Tu, S.; Lenahan, C.; Shao, A.; Sheng, J. Pathophysiology and Therapeutic Potential of NADPH Oxidases in Ischemic Stroke-Induced Oxidative Stress. Oxidative Med. Cell. Longev. 2021, 2021, 6631805. [Google Scholar] [CrossRef] [PubMed]
- Magnani, F.; Mattevi, A. Structure and mechanisms of ROS generation by NADPH oxidases. Curr. Opin. Struct. Biol. 2019, 59, 91–97. [Google Scholar] [CrossRef] [PubMed]
- Leto, T.L.; Morand, S.; Hurt, D.; Ueyama, T. Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases. Antioxid. Redox Signal. 2009, 11, 2607–2619. [Google Scholar] [CrossRef] [PubMed]
- Schroder, K. NADPH oxidases: Current aspects and tools. Redox Biol. 2020, 34, 101512. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Murugesan, P.; Huang, K.; Cai, H. NADPH oxidases and oxidase crosstalk in cardiovascular diseases: Novel therapeutic targets. Nat. Rev. Cardiol. 2020, 17, 170–194. [Google Scholar] [CrossRef] [PubMed]
- Lee, S.H.; Lee, M.; Ko, D.G.; Choi, B.Y.; Suh, S.W. The Role of NADPH Oxidase in Neuronal Death and Neurogenesis after Acute Neurological Disorders. Antioxidants 2021, 10, 739. [Google Scholar] [CrossRef] [PubMed]
- Bortolotti, M.; Polito, L.; Battelli, M.G.; Bolognesi, A. Xanthine oxidoreductase: One enzyme for multiple physiological tasks. Redox Biol. 2021, 41, 101882. [Google Scholar] [CrossRef] [PubMed]
- Berry, C.E.; Hare, J.M. Xanthine oxidoreductase and cardiovascular disease: Molecular mechanisms and pathophysiological implications. J. Physiol. 2004, 555, 589–606. [Google Scholar] [CrossRef] [PubMed]
- Schmidt, H.M.; DeVallance, E.R.; Lewis, S.E.; Wood, K.C.; Annarapu, G.K.; Carreno, M.; Hahn, S.A.; Seman, M.; Maxwell, B.A.; Hileman, E.A.; et al. Release of hepatic xanthine oxidase (XO) to the circulation is protective in intravascular hemolytic crisis. Redox Biol. 2023, 62, 102636. [Google Scholar] [CrossRef]
- Washio, K.; Kusunoki, Y.; Tsunoda, T.; Osugi, K.; Ohigashi, M.; Murase, T.; Nakamura, T.; Matsuo, T.; Konishi, K.; Katsuno, T.; et al. Xanthine oxidoreductase activity correlates with vascular endothelial dysfunction in patients with type 1 diabetes. Acta Diabetol. 2020, 57, 31–39. [Google Scholar] [CrossRef]
- Yang, K.J.; Choi, W.J.; Chang, Y.K.; Park, C.W.; Kim, S.Y.; Hong, Y.A. Inhibition of Xanthine Oxidase Protects against Diabetic Kidney Disease through the Amelioration of Oxidative Stress via VEGF/VEGFR Axis and NOX-FoxO3a-eNOS Signaling Pathway. Int. J. Mol. Sci. 2023, 24, 3807. [Google Scholar] [CrossRef] [PubMed]
- Kim, N.H.; Hong, B.K.; Choi, S.Y.; Moo Kwon, H.; Cho, C.S.; Yi, E.C.; Kim, W.U. Reactive oxygen species regulate context-dependent inhibition of NFAT5 target genes. Exp. Mol. Med. 2013, 45, e32. [Google Scholar] [CrossRef] [PubMed]
- Kakimoto, M.; Fujii, M.; Sato, I.; Honma, K.; Nakayama, H.; Kirihara, S.; Fukuoka, T.; Ran, S.; Hirohata, S.; Kitamori, K.; et al. Antioxidant action of xanthine oxidase inhibitor febuxostat protects the liver and blood vasculature in SHRSP5/Dmcr rats. J. Appl. Biomed. 2023, 21, 80–90. [Google Scholar] [CrossRef] [PubMed]
- Katusic, Z.S.; d’Uscio, L.V.; Nath, K.A. Vascular protection by tetrahydrobiopterin: Progress and therapeutic prospects. Trends Pharmacol. Sci. 2009, 30, 48–54. [Google Scholar] [CrossRef]
- Karbach, S.; Wenzel, P.; Waisman, A.; Munzel, T.; Daiber, A. eNOS uncoupling in cardiovascular diseases--the role of oxidative stress and inflammation. Curr. Pharm. Des. 2014, 20, 3579–3594. [Google Scholar] [CrossRef]
- Janaszak-Jasiecka, A.; Siekierzycka, A.; Płoska, A.; Dobrucki, I.T.; Kalinowski, L. Endothelial Dysfunction Driven by Hypoxia—The Influence of Oxygen Deficiency on NO Bioavailability. Biomolecules 2021, 11, 982. [Google Scholar] [CrossRef]
- Li, H.; Xia, N.; Hasselwander, S.; Daiber, A. Resveratrol and Vascular Function. Int. J. Mol. Sci. 2019, 20, 2155. [Google Scholar] [CrossRef]
- Xia, N.; Forstermann, U.; Li, H. Resveratrol and endothelial nitric oxide. Molecules 2014, 19, 16102–16121. [Google Scholar] [CrossRef]
- Yang, Y.-M.; Huang, A.; Kaley, G.; Sun, D. eNOS uncoupling and endothelial dysfunction in aged vessels. Am. J. Physiol. Heart Circ. Physiol. 2009, 297, H1829–H1836. [Google Scholar] [CrossRef]
- De Pascali, F.; Hemann, C.; Samons, K.; Chen, C.A.; Zweier, J.L. Hypoxia and reoxygenation induce endothelial nitric oxide synthase uncoupling in endothelial cells through tetrahydrobiopterin depletion and S-glutathionylation. Biochemistry 2014, 53, 3679–3688. [Google Scholar] [CrossRef]
- Galougahi, K.K.; Liu, C.C.; Gentile, C.; Kok, C.; Nunez, A.; Garcia, A.; Fry, N.A.S.; Davies, M.J.; Hawkins, C.L.; Rasmussen, H.H.; et al. Glutathionylation Mediates Angiotensin II–Induced eNOS Uncoupling, Amplifying NADPH Oxidase-Dependent Endothelial Dysfunction. J. Am. Heart Assoc. 2014, 3, e000731. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Janssens, S.P.; Wingler, K.; Schmidt, H.H.H.W.; Moens, A.L. Modulating endothelial nitric oxide synthase: A new cardiovascular therapeutic strategy. Am. J. Physiol. Heart Circ. Physiol. 2011, 301, H634–H646. [Google Scholar] [CrossRef] [PubMed]
- Wang, L.; Zeng, W.; Wang, C.; Lu, Y.; Xiong, X.; Chen, S.; Huang, Q.; Yan, F.; Huang, Q. SUMOylation and coupling of eNOS mediated by PIAS1 contribute to maintenance of vascular homeostasis. FASEB J. 2024, 38, e23362. [Google Scholar] [CrossRef] [PubMed]
- Singh, U.; Devaraj, S.; Vasquez-Vivar, J.; Jialal, I. C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling. J. Mol. Cell. Cardiol. 2007, 43, 780–791. [Google Scholar] [CrossRef] [PubMed]
- Shaito, A.; Aramouni, K.; Assaf, R.; Parenti, A.; Orekhov, A.; Yazbi, A.E.; Pintus, G.; Eid, A.H. Oxidative Stress-Induced Endothelial Dysfunction in Cardiovascular Diseases. Front. Biosci. 2022, 27, 105. [Google Scholar] [CrossRef] [PubMed]
- Stowe, D.F.; Camara, A.K. Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function. Antioxid. Redox Signal. 2009, 11, 1373–1414. [Google Scholar] [CrossRef] [PubMed]
- Ortiz, D.; Forquer, I.; Boitz, J.; Soysa, R.; Elya, C.; Fulwiler, A.; Nilsen, A.; Polley, T.; Riscoe, M.K.; Ullman, B.; et al. Targeting the Cytochrome bc1 Complex of Leishmania Parasites for Discovery of Novel Drugs. Antimicrob. Agents Chemother. 2016, 60, 4972–4982. [Google Scholar] [CrossRef] [PubMed]
- Tseyang, T.; Valeros, J.; Vo, P.; Spinelli, J.B. Oxygen-Independent Assays to Measure Mitochondrial Function in Mammals. J. Vis. Exp. 2023, e65184. [Google Scholar] [CrossRef] [PubMed]
- Chua, Y.L.; Hagen, T. Compound C prevents Hypoxia-Inducible Factor-1α protein stabilization by regulating the cellular oxygen availability via interaction with Mitochondrial Complex I. BMC Res. Notes 2011, 4, 117. [Google Scholar] [CrossRef]
- Chua, Y.L.; Dufour, E.; Dassa, E.P.; Rustin, P.; Jacobs, H.T.; Taylor, C.T.; Hagen, T. Stabilization of hypoxia-inducible factor-1α protein in hypoxia occurs independently of mitochondrial reactive oxygen species production. J. Biol. Chem. 2010, 285, 31277–31284. [Google Scholar] [CrossRef]
- Giacco, F.; Brownlee, M. Oxidative stress and diabetic complications. Circ. Res. 2010, 107, 1058–1070. [Google Scholar] [CrossRef] [PubMed]
- Hroudova, J.; Singh, N.; Fisar, Z. Mitochondrial dysfunctions in neurodegenerative diseases: Relevance to Alzheimer’s disease. BioMed Res. Int. 2014, 2014, 175062. [Google Scholar] [CrossRef]
- Chen, Q.; Camara, A.K.; Stowe, D.F.; Hoppel, C.L.; Lesnefsky, E.J. Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion. Am. J. Physiol. Cell Physiol. 2007, 292, C137–C147. [Google Scholar] [CrossRef] [PubMed]
- Fujita, N.; Momota, M.; Ishida, M.; Iwane, T.; Hatakeyama, S.; Yoneyama, T.; Hashimoto, Y.; Yoshikawa, K.; Yamaya, K.; Ohyama, C. Association of oxidative stress with erectile dysfunction in community-dwelling men and men on dialysis. Aging Male 2022, 25, 193–201. [Google Scholar] [CrossRef]
- Trebaticky, B.; Zitnanova, I.; Dvorakova, M.; Orszaghova, Z.; Paduchova, Z.; Durackova, Z.; Breza, J.; Muchova, J. Role of oxidative stress, adiponectin and endoglin in the pathophysiology of erectile dysfunction in diabetic and non-diabetic men. Physiol. Res. 2019, 68, 623–631. [Google Scholar] [CrossRef]
- Yu, W.; Wang, J.; Dai, Y.T.; Wang, B.; Xu, Y.; Gao, Q.Q.; Xu, Z.P. Modulation of SIRT1 expression improves erectile function in aged rats. Asian J. Androl. 2022, 24, 666–670. [Google Scholar] [CrossRef]
- Johnson, J.M.; Bivalacqua, T.J.; Lagoda, G.A.; Burnett, A.L.; Musicki, B. eNOS-uncoupling in age-related erectile dysfunction. Int. J. Impot. Res. 2011, 23, 43–48. [Google Scholar] [CrossRef]
- Ferrini, M.G.; Davila, H.H.; Valente, E.G.; Gonzalez-Cadavid, N.F.; Rajfer, J. Aging-related induction of inducible nitric oxide synthase is vasculo-protective to the arterial media. Cardiovasc. Res. 2004, 61, 796–805. [Google Scholar] [CrossRef] [PubMed]
- Bivalacqua, T.J.; Armstrong, J.S.; Biggerstaff, J.; Abdel-Mageed, A.B.; Kadowitz, P.J.; Hellstrom, W.J.; Champion, H.C. Gene transfer of extracellular SOD to the penis reduces O2-* and improves erectile function in aged rats. Am. J. Physiol. Heart Circ. Physiol. 2003, 284, H1408–H1421. [Google Scholar] [CrossRef]
- Ferrini, M.; Magee, T.R.; Vernet, D.; Rajfer, J.; Gonzalez-Cadavid, N.F. Aging-related expression of inducible nitric oxide synthase and markers of tissue damage in the rat penis. Biol. Reprod. 2001, 64, 974–982. [Google Scholar] [CrossRef]
- Shi, J.P.; Zhao, Y.M.; Song, Y.T. Effect of aging on expression of nitric oxide synthase I and activity of nitric oxide synthase in rat penis. Asian J. Androl. 2003, 5, 117–120. [Google Scholar] [PubMed]
- Gandhi, J.; Dagur, G.; Warren, K.; Smith, N.L.; Sheynkin, Y.R.; Zumbo, A.; Khan, S.A. The Role of Diabetes Mellitus in Sexual and Reproductive Health: An Overview of Pathogenesis, Evaluation, and Management. Curr. Diabetes Rev. 2017, 13, 573–581. [Google Scholar] [CrossRef] [PubMed]
- Burnett, A.L.; Strong, T.D.; Trock, B.J.; Jin, L.; Bivalacqua, T.J.; Musicki, B. Serum biomarker measurements of endothelial function and oxidative stress after daily dosing of sildenafil in type 2 diabetic men with erectile dysfunction. J. Urol. 2009, 181, 245–251. [Google Scholar] [CrossRef] [PubMed]
- Costa, C.; Soares, R.; Castela, A.; Adaes, S.; Hastert, V.; Vendeira, P.; Virag, R. Increased endothelial apoptotic cell density in human diabetic erectile tissue—comparison with clinical data. J. Sex. Med. 2009, 6, 826–835. [Google Scholar] [CrossRef] [PubMed]
- Esposito, K.; Ciotola, M.; Giugliano, F.; Sardelli, L.; Giugliano, F.; Maiorino, M.I.; Beneduce, F.; De Sio, M.; Giugliano, D. Phenotypic assessment of endothelial microparticles in diabetic and nondiabetic men with erectile dysfunction. J. Sex. Med. 2008, 5, 1436–1442. [Google Scholar] [CrossRef] [PubMed]
- Tuncayengin, A.; Biri, H.; Onaran, M.; Sen, I.; Tuncayengin, O.; Polat, F.; Erbas, D.; Bozkirli, I. Cavernosal tissue nitrite, nitrate, malondialdehyde and glutathione levels in diabetic and non-diabetic erectile dysfunction. Int. J. Androl. 2003, 26, 250–254. [Google Scholar] [CrossRef] [PubMed]
- Wan, Z.H.; Li, W.Z.; Li, Y.Z.; Chen, L.; Li, G.H.; Hu, W.F.; Peng, S.; Yu, J.J.; Guo, F. Poly(ADP-Ribose) polymerase inhibition improves erectile function in diabetic rats. J. Sex. Med. 2011, 8, 1002–1014. [Google Scholar] [CrossRef] [PubMed]
- Angulo, J.; Peiro, C.; Cuevas, P.; Gabancho, S.; Fernandez, A.; Gonzalez-Corrochano, R.; La Fuente, J.M.; Baron, A.D.; Chen, K.S.; de Tejada, I.S. The novel antioxidant, AC3056 (2,6-di-t-butyl-4-((dimethyl-4-methoxyphenylsilyl)methyloxy)phenol), reverses erectile dysfunction in diabetic rats and improves NO-mediated responses in penile tissue from diabetic men. J. Sex. Med. 2009, 6, 373–387. [Google Scholar] [CrossRef] [PubMed]
- Jin, H.R.; Kim, W.J.; Song, J.S.; Choi, M.J.; Piao, S.; Shin, S.H.; Tumurbaatar, M.; Tuvshintur, B.; Nam, M.S.; Ryu, J.K.; et al. Functional and morphologic characterizations of the diabetic mouse corpus cavernosum: Comparison of a multiple low-dose and a single high-dose streptozotocin protocols. J. Sex. Med. 2009, 6, 3289–3304. [Google Scholar] [CrossRef]
- Shukla, N.; Hotston, M.; Persad, R.; Angelini, G.D.; Jeremy, J.Y. The administration of folic acid improves erectile function and reduces intracavernosal oxidative stress in the diabetic rabbit. BJU Int. 2009, 103, 98–103. [Google Scholar] [CrossRef]
- Bivalacqua, T.J.; Usta, M.F.; Kendirci, M.; Pradhan, L.; Alvarez, X.; Champion, H.C.; Kadowitz, P.J.; Hellstrom, W.J. Superoxide anion production in the rat penis impairs erectile function in diabetes: Influence of in vivo extracellular superoxide dismutase gene therapy. J. Sex. Med. 2005, 2, 187–197; discussion 197–198. [Google Scholar] [CrossRef] [PubMed]
- De Young, L.; Yu, D.; Bateman, R.M.; Brock, G.B. Oxidative stress and antioxidant therapy: Their impact in diabetes-associated erectile dysfunction. J. Androl. 2004, 25, 830–836. [Google Scholar] [CrossRef]
- Paskaloglu, K.; Sener, G.; Ayangolu-Dulger, G. Melatonin treatment protects against diabetes-induced functional and biochemical changes in rat aorta and corpus cavernosum. Eur. J. Pharmacol. 2004, 499, 345–354. [Google Scholar] [CrossRef] [PubMed]
- Ryu, J.K.; Kim, D.J.; Lee, T.; Kang, Y.S.; Yoon, S.M.; Suh, J.K. The role of free radical in the pathogenesis of impotence in streptozotocin-induced diabetic rats. Yonsei Med. J. 2003, 44, 236–241. [Google Scholar] [CrossRef] [PubMed]
- Fatehi-Hassanabad, Z.; Chan, C.B.; Furman, B.L. Reactive oxygen species and endothelial function in diabetes. Eur. J. Pharmacol. 2010, 636, 8–17. [Google Scholar] [CrossRef] [PubMed]
- Picchi, A.; Capobianco, S.; Qiu, T.; Focardi, M.; Zou, X.; Cao, J.M.; Zhang, C. Coronary microvascular dysfunction in diabetes mellitus: A review. World J. Cardiol. 2010, 2, 377–390. [Google Scholar] [CrossRef] [PubMed]
- Musicki, B.; Kramer, M.F.; Becker, R.E.; Burnett, A.L. Inactivation of phosphorylated endothelial nitric oxide synthase (Ser-1177) by O-GlcNAc in diabetes-associated erectile dysfunction. Proc. Natl. Acad. Sci. USA 2005, 102, 11870–11875. [Google Scholar] [CrossRef]
- Keegan, A.; Jack, A.M.; Cotter, M.A.; Cameron, N.E. Effects of aldose reductase inhibition on responses of the corpus cavernosum and mesenteric vascular bed of diabetic rats. J. Cardiovasc. Pharmacol. 2000, 35, 606–613. [Google Scholar] [CrossRef]
- Nangle, M.R.; Cotter, M.A.; Cameron, N.E. Poly(ADP-ribose) polymerase inhibition reverses nitrergic neurovascular dysfunctions in penile erectile tissue from streptozotocin-diabetic mice. J. Sex. Med. 2010, 7, 3396–3403. [Google Scholar] [CrossRef]
- Nangle, M.R.; Cotter, M.A.; Cameron, N.E. IκB kinase 2 inhibition corrects defective nitrergic erectile mechanisms in diabetic mouse corpus cavernosum. Urology 2006, 68, 214–218. [Google Scholar] [CrossRef]
- Jin, H.R.; Kim, W.J.; Song, J.S.; Piao, S.; Choi, M.J.; Tumurbaatar, M.; Shin, S.H.; Yin, G.N.; Koh, G.Y.; Ryu, J.K.; et al. Intracavernous delivery of a designed angiopoietin-1 variant rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse. Diabetes 2011, 60, 969–980. [Google Scholar] [CrossRef]
- Chitaley, K.; Kupelian, V.; Subak, L.; Wessells, H. Diabetes, obesity and erectile dysfunction: Field overview and research priorities. J. Urol. 2009, 182, S45–S50. [Google Scholar] [CrossRef]
- Kovanecz, I.; Ferrini, M.G.; Vernet, D.; Nolazco, G.; Rajfer, J.; Gonzalez-Cadavid, N.F. Pioglitazone prevents corporal veno-occlusive dysfunction in a rat model of type 2 diabetes mellitus. BJU Int. 2006, 98, 116–124. [Google Scholar] [CrossRef]
- Cellek, S.; Qu, W.; Schmidt, A.M.; Moncada, S. Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: A new insight into selective nitrergic neuropathy in diabetes. Diabetologia 2004, 47, 331–339. [Google Scholar] [CrossRef]
- Cellek, S.; Foxwell, N.A.; Moncada, S. Two phases of nitrergic neuropathy in streptozotocin-induced diabetic rats. Diabetes 2003, 52, 2353–2362. [Google Scholar] [CrossRef]
- Kloner, R. Erectile dysfunction and hypertension. Int. J. Impot. Res. 2007, 19, 296–302. [Google Scholar] [CrossRef] [PubMed]
- Touyz, R.M. Intracellular mechanisms involved in vascular remodelling of resistance arteries in hypertension: Role of angiotensin II. Exp. Physiol. 2005, 90, 449–455. [Google Scholar] [CrossRef] [PubMed]
- Ushiyama, M.; Morita, T.; Kuramochi, T.; Yagi, S.; Katayama, S. Erectile dysfunction in hypertensive rats results from impairment of the relaxation evoked by neurogenic carbon monoxide and nitric oxide. Hypertens. Res. 2004, 27, 253–261. [Google Scholar] [CrossRef] [PubMed]
- Ushiyama, M.; Kuramochi, T.; Yagi, S.; Katayama, S. Antioxidant treatment with α-tocopherol improves erectile function in hypertensive rats. Hypertens. Res. 2008, 31, 1007–1013. [Google Scholar] [CrossRef]
- Claudino, M.A.; Franco-Penteado, C.F.; Priviero, F.B.; Camargo, E.A.; Teixeira, S.A.; Muscara, M.N.; De Nucci, G.; Zanesco, A.; Antunes, E. Upregulation of gp91phox subunit of NAD(P)H oxidase contributes to erectile dysfunction caused by long-term nitric oxide inhibition in rats: Reversion by regular physical training. Urology 2010, 75, 961–967. [Google Scholar] [CrossRef] [PubMed]
- Jin, L.; Lagoda, G.; Leite, R.; Webb, R.C.; Burnett, A.L. NADPH oxidase activation: A mechanism of hypertension-associated erectile dysfunction. J. Sex. Med. 2008, 5, 544–551. [Google Scholar] [CrossRef] [PubMed]
- Jeremy, J.Y.; Jones, R.A.; Koupparis, A.J.; Hotston, M.; Persad, R.; Angelini, G.D.; Shukla, N. Reactive oxygen species and erectile dysfunction: Possible role of NADPH oxidase. Int. J. Impot. Res. 2007, 19, 265–280. [Google Scholar] [CrossRef] [PubMed]
- Li, R.; Cui, K.; Wang, T.; Wang, S.; Li, X.; Qiu, J.; Yu, G.; Liu, J.; Wen, B.; Rao, K. Hyperlipidemia impairs erectile function in rats by causing cavernosal fibrosis. Andrologia 2017, 49, e12693. [Google Scholar] [CrossRef] [PubMed]
- Lee, J.H.; Oh, J.H.; Lee, Y.J. Effects of experimental hyperlipidemia on the pharmacokinetics of tadalafil in rats. J. Pharm. Pharm. Sci. 2012, 15, 528–537. [Google Scholar] [CrossRef] [PubMed]
- Huang, Y.C.; Ning, H.; Shindel, A.W.; Fandel, T.M.; Lin, G.; Harraz, A.M.; Lue, T.F.; Lin, C.S. The effect of intracavernous injection of adipose tissue-derived stem cells on hyperlipidemia-associated erectile dysfunction in a rat model. J. Sex. Med. 2010, 7, 1391–1400. [Google Scholar] [CrossRef] [PubMed]
- Musicki, B.; Liu, T.; Lagoda, G.A.; Strong, T.D.; Sezen, S.F.; Johnson, J.M.; Burnett, A.L. Hypercholesterolemia-induced erectile dysfunction: Endothelial nitric oxide synthase (eNOS) uncoupling in the mouse penis by NAD(P)H oxidase. J. Sex. Med. 2010, 7, 3023–3032. [Google Scholar] [CrossRef]
- Musicki, B.; Liu, T.; Strong, T.; Jin, L.; Laughlin, M.H.; Turk, J.R.; Burnett, A.L. Low-fat diet and exercise preserve eNOS regulation and endothelial function in the penis of early atherosclerotic pigs: A molecular analysis. J. Sex. Med. 2008, 5, 552–561. [Google Scholar] [CrossRef]
- Shukla, N.; Jones, R.; Persad, R.; Angelini, G.D.; Jeremy, J.Y. Effect of sildenafil citrate and a nitric oxide donating sildenafil derivative, NCX 911, on cavernosal relaxation and superoxide formation in hypercholesterolaemic rabbits. Eur. J. Pharmacol. 2005, 517, 224–231. [Google Scholar] [CrossRef]
- Zouaoui Boudjeltia, K.; Roumeguere, T.; Delree, P.; Moguilevsky, N.; Ducobu, J.; Vanhaeverbeek, M.; Wespes, E. Presence of LDL modified by myeloperoxidase in the penis in patients with vascular erectile dysfunction: A preliminary study. Eur. Urol. 2007, 51, 262–268; discussion 268–269. [Google Scholar] [CrossRef] [PubMed]
- Schulz, E.; Anter, E.; Keaney, J.F., Jr. Oxidative stress, antioxidants, and endothelial function. Curr. Med. Chem. 2004, 11, 1093–1104. [Google Scholar] [CrossRef] [PubMed]
- Zhong, L.; Ding, W.; Zeng, Q.; He, B.; Zhang, H.; Wang, L.; Fan, J.; He, S.; Zhang, Y.; Wei, A. Sodium Tanshinone IIA Sulfonate Attenuates Erectile Dysfunction in Rats with Hyperlipidemia. Oxid. Med. Cell Longev. 2020, 2020, 7286958. [Google Scholar] [CrossRef] [PubMed]
- Podkowinska, A.; Formanowicz, D. Chronic Kidney Disease as Oxidative Stress- and Inflammatory-Mediated Cardiovascular Disease. Antioxidants 2020, 9, 752. [Google Scholar] [CrossRef] [PubMed]
- Carlstrom, M. Nitric oxide signalling in kidney regulation and cardiometabolic health. Nat. Rev. Nephrol. 2021, 17, 575–590. [Google Scholar] [CrossRef] [PubMed]
- Duni, A.; Liakopoulos, V.; Roumeliotis, S.; Peschos, D.; Dounousi, E. Oxidative Stress in the Pathogenesis and Evolution of Chronic Kidney Disease: Untangling Ariadne’s Thread. Int. J. Mol. Sci. 2019, 20, 3711. [Google Scholar] [CrossRef] [PubMed]
- Roumeliotis, S.; Mallamaci, F.; Zoccali, C. Endothelial Dysfunction in Chronic Kidney Disease, from Biology to Clinical Outcomes: A 2020 Update. J. Clin. Med. 2020, 9, 2359. [Google Scholar] [CrossRef] [PubMed]
- Fontecha-Barriuso, M.; Lopez-Diaz, A.M.; Guerrero-Mauvecin, J.; Miguel, V.; Ramos, A.M.; Sanchez-Nino, M.D.; Ruiz-Ortega, M.; Ortiz, A.; Sanz, A.B. Tubular Mitochondrial Dysfunction, Oxidative Stress, and Progression of Chronic Kidney Disease. Antioxidants 2022, 11, 1356. [Google Scholar] [CrossRef]
- Jabarpour, M.; Rashtchizadeh, N.; Argani, H.; Ghorbanihaghjo, A.; Ranjbarzadhag, M.; Sanajou, D.; Panah, F.; Alirezaei, A. The impact of dyslipidemia and oxidative stress on vasoactive mediators in patients with renal dysfunction. Int. Urol. Nephrol. 2019, 51, 2235–2242. [Google Scholar] [CrossRef] [PubMed]
- Allen, M.S.; Tostes, R.C. Cigarette smoking and erectile dysfunction: An updated review with a focus on pathophysiology, e-cigarettes, and smoking cessation. Sex. Med. Rev. 2023, 11, 61–73. [Google Scholar] [CrossRef]
- Dikalov, S.; Itani, H.; Richmond, B.; Vergeade, A.; Rahman, S.M.J.; Boutaud, O.; Blackwell, T.; Massion, P.P.; Harrison, D.G.; Dikalova, A. Tobacco smoking induces cardiovascular mitochondrial oxidative stress, promotes endothelial dysfunction, and enhances hypertension. Am. J. Physiol. Heart Circ. Physiol. 2019, 316, H639–H646. [Google Scholar] [CrossRef]
- Barbieri, S.S.; Zacchi, E.; Amadio, P.; Gianellini, S.; Mussoni, L.; Weksler, B.B.; Tremoli, E. Cytokines present in smokers’ serum interact with smoke components to enhance endothelial dysfunction. Cardiovasc. Res. 2011, 90, 475–483. [Google Scholar] [CrossRef]
- Imamura, M.; Waseda, Y.; Marinova, G.V.; Ishibashi, T.; Obayashi, S.; Sasaki, A.; Nagai, A.; Azuma, H. Alterations of NOS, arginase, and DDAH protein expression in rabbit cavernous tissue after administration of cigarette smoke extract. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007, 293, R2081–R2089. [Google Scholar] [CrossRef] [PubMed]
- Lin, J.H.; Ho, D.R.; Shi, C.S.; Chen, C.S.; Li, J.M.; Huang, Y.C. The influence of smoking exposure and cessation on penile hemodynamics and corporal tissue in a rat model. Transl. Androl. Urol. 2020, 9, 637–645. [Google Scholar] [CrossRef]
- Hotston, M.R.; Jeremy, J.Y.; Bloor, J.; Koupparis, A.; Persad, R.; Shukla, N. Sildenafil inhibits the up-regulation of phosphodiesterase type 5 elicited with nicotine and tumour necrosis factor-α in cavernosal vascular smooth muscle cells: Mediation by superoxide. BJU Int. 2007, 99, 612–618. [Google Scholar] [CrossRef]
- Virdis, A.; Masi, S.; Colucci, R.; Chiriaco, M.; Uliana, M.; Puxeddu, I.; Bernardini, N.; Blandizzi, C.; Taddei, S. Microvascular Endothelial Dysfunction in Patients with Obesity. Curr. Hypertens. Rep. 2019, 21, 32. [Google Scholar] [CrossRef]
- Marseglia, L.; Manti, S.; D’Angelo, G.; Nicotera, A.; Parisi, E.; Di Rosa, G.; Gitto, E.; Arrigo, T. Oxidative stress in obesity: A critical component in human diseases. Int. J. Mol. Sci. 2014, 16, 378–400. [Google Scholar] [CrossRef] [PubMed]
- Kajikawa, M.; Higashi, Y. Obesity and Endothelial Function. Biomedicines 2022, 10, 1745. [Google Scholar] [CrossRef]
- Paduch, D.A.; Bolyakov, A.; Vaucher, L. Obesity and sexual dysfunction in men. In Obesity and Gynecology; Elsevier: Amsterdam, The Netherlands, 2020. [Google Scholar]
- Soardo, G.; Donnini, D.; Varutti, R.; Moretti, M.; Milocco, C.; Basan, L.; Esposito, W.; Casaccio, D.; Stel, G.; Catena, C.; et al. Alcohol-induced endothelial changes are associated with oxidative stress and are rapidly reversed after withdrawal. Alcohol. Clin. Exp. Res. 2005, 29, 1889–1898. [Google Scholar] [CrossRef]
- Phillips, S.A.; Osborn, K.; Hwang, C.L.; Sabbahi, A.; Piano, M.R. Ethanol Induced Oxidative Stress in the Vasculature: Friend or Foe. Curr. Hypertens. Rev. 2020, 16, 181–191. [Google Scholar] [CrossRef]
- Tan, H.K.; Yates, E.; Lilly, K.; Dhanda, A.D. Oxidative stress in alcohol-related liver disease. World J. Hepatol. 2020, 12, 332–349. [Google Scholar] [CrossRef]
- Finelli, R.; Mottola, F.; Agarwal, A. Impact of Alcohol Consumption on Male Fertility Potential: A Narrative Review. Int. J. Environ. Res. Public Health 2021, 19, 328. [Google Scholar] [CrossRef]
- Kamal, H.; Tan, G.C.; Ibrahim, S.F.; Shaikh, M.F.; Mohamed, I.N.; Mohamed, R.M.P.; Hamid, A.A.; Ugusman, A.; Kumar, J. Alcohol Use Disorder, Neurodegeneration, Alzheimer’s and Parkinson’s Disease: Interplay Between Oxidative Stress, Neuroimmune Response and Excitotoxicity. Front. Cell Neurosci. 2020, 14, 282. [Google Scholar] [CrossRef] [PubMed]
- Li, S.; Song, J.M.; Zhang, K.; Zhang, C.L. A Meta-Analysis of Erectile Dysfunction and Alcohol Consumption. Urol. Int. 2021, 105, 969–985. [Google Scholar] [CrossRef] [PubMed]
- Karunakaran, A.; Prabhakaran, A.; Karunakaran, V.; Michael, J.P. Erectile Dysfunction in Alcohol Use Disorder and the change in erectile function after one month of abstinence. J. Addict. Dis. 2024, 42, 112–121. [Google Scholar] [CrossRef] [PubMed]
- Tsigos, C.; Kyrou, I.; Kassi, E.; Chrousos, G.P. Stress: Endocrine Physiology and Pathophysiology; Feingold, K.R., Anawalt, B., Blackman, M.R., Boyce, A., Chrousos, G., Corpas, E., de Herder, W.W., Dhatariya, K., Dungan, K., Hofland, J., et al., Eds.; Endotext: South Dartmouth, MA, USA, 2000. [Google Scholar]
- Chu, B.; Marwaha, K.; Sanvictores, T.; Awosika, A.O.; Ayers, D. Physiology, Stress Reaction; StatPearls: Treasure Island, FL, USA, 2024. [Google Scholar]
- Salim, S. Oxidative stress and psychological disorders. Curr. Neuropharmacol. 2014, 12, 140–147. [Google Scholar] [CrossRef] [PubMed]
- Schiavone, S.; Sorce, S.; Dubois-Dauphin, M.; Jaquet, V.; Colaianna, M.; Zotti, M.; Cuomo, V.; Trabace, L.; Krause, K.H. Involvement of NOX2 in the development of behavioral and pathologic alterations in isolated rats. Biol. Psychiatry 2009, 66, 384–392. [Google Scholar] [CrossRef] [PubMed]
- Xiao, Y.; Xie, T.; Peng, J.; Zhou, X.; Long, J.; Yang, M.; Zhu, H.; Yang, J. Factors associated with anxiety and depression in patients with erectile dysfunction: A cross-sectional study. BMC Psychol. 2023, 11, 36. [Google Scholar] [CrossRef] [PubMed]
- Salvio, G.; Ciarloni, A.; Cutini, M.; Balercia, G. Hyperhomocysteinemia: Focus on Endothelial Damage as a Cause of Erectile Dysfunction. Int. J. Mol. Sci. 2021, 22, 418. [Google Scholar] [CrossRef] [PubMed]
- Koupparis, A.J.; Jeremy, J.; Angelini, G.; Persad, R.; Shukla, N. Penicillamine administration reverses the inhibitory effect of hyperhomocysteinaemia on endothelium-dependent relaxation in the corpus cavernosum in the rabbit. BJU Int. 2006, 98, 440–444. [Google Scholar] [CrossRef] [PubMed]
- Jones, R.W.; Jeremy, J.Y.; Koupparis, A.; Persad, R.; Shukla, N. Cavernosal dysfunction in a rabbit model of hyperhomocysteinaemia. BJU Int. 2005, 95, 125–130. [Google Scholar] [CrossRef]
- Kato, G.J.; Hebbel, R.P.; Steinberg, M.H.; Gladwin, M.T. Vasculopathy in sickle cell disease: Biology, pathophysiology, genetics, translational medicine, and new research directions. Am. J. Hematol. 2009, 84, 618–625. [Google Scholar] [CrossRef]
- Nader, E.; Romana, M.; Connes, P. The Red Blood Cell—Inflammation Vicious Circle in Sickle Cell Disease. Front. Immunol. 2020, 11, 454. [Google Scholar] [CrossRef]
- Chirico, E.N.; Pialoux, V. Role of oxidative stress in the pathogenesis of sickle cell disease. IUBMB Life 2012, 64, 72–80. [Google Scholar] [CrossRef] [PubMed]
- Wood, K.C.; Hsu, L.L.; Gladwin, M.T. Sickle cell disease vasculopathy: A state of nitric oxide resistance. Free Radic. Biol. Med. 2008, 44, 1506–1528. [Google Scholar] [CrossRef]
- Idris, I.M.; Burnett, A.L.; DeBaun, M.R. Epidemiology and treatment of priapism in sickle cell disease. Hematol. Am. Soc. Hematol. Educ. Program 2022, 2022, 450–458. [Google Scholar] [CrossRef] [PubMed]
- Chinegwundoh, F.I.; Smith, S.; Anie, K.A. Treatments for priapism in boys and men with sickle cell disease. Cochrane Database Syst. Rev. 2020, 4, CD004198. [Google Scholar] [CrossRef] [PubMed]
- Kanika, N.D.; Melman, A.; Davies, K.P. Experimental priapism is associated with increased oxidative stress and activation of protein degradation pathways in corporal tissue. Int. J. Impot. Res. 2010, 22, 363–373. [Google Scholar] [CrossRef] [PubMed]
- Agarwal, A.; Nandipati, K.C.; Sharma, R.K.; Zippe, C.D.; Raina, R. Role of oxidative stress in the pathophysiological mechanism of erectile dysfunction. J. Androl. 2006, 27, 335–347. [Google Scholar] [CrossRef]
- Azadzoi, K.M.; Golabek, T.; Radisavljevic, Z.M.; Yalla, S.V.; Siroky, M.B. Oxidative stress and neurodegeneration in penile ischaemia. BJU Int. 2010, 105, 404–410. [Google Scholar] [CrossRef]
- Uluocak, N.; Atilgan, D.; Erdemir, F.; Parlaktas, B.S.; Yasar, A.; Erkorkmaz, U.; Akbas, A. An animal model of ischemic priapism and the effects of melatonin on antioxidant enzymes and oxidative injury parameters in rat penis. Int. Urol. Nephrol. 2010, 42, 889–895. [Google Scholar] [CrossRef]
- Lagoda, G.; Jin, L.; Lehrfeld, T.J.; Liu, T.; Burnett, A.L. FK506 and sildenafil promote erectile function recovery after cavernous nerve injury through antioxidative mechanisms. J. Sex. Med. 2007, 4, 908–916. [Google Scholar] [CrossRef]
- Yeni, E.; Gulum, M.; Selek, S.; Erel, O.; Unal, D.; Verit, A.; Savas, M. Comparison of oxidative/antioxidative status of penile corpus cavernosum blood and peripheral venous blood. Int. J. Impot. Res. 2005, 17, 19–22. [Google Scholar] [CrossRef] [PubMed]
- Kawakami, T.; Urakami, S.; Hirata, H.; Tanaka, Y.; Nakajima, K.; Enokida, H.; Shiina, H.; Ogishima, T.; Tokizane, T.; Kawamoto, K.; et al. Superoxide dismutase analog (Tempol: 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine 1-oxyl) treatment restores erectile function in diabetes-induced impotence. Int. J. Impot. Res. 2009, 21, 348–355. [Google Scholar] [CrossRef]
- Kim, S.C.; Kim, I.K.; Seo, K.K.; Baek, K.J.; Lee, M.Y. Involvement of superoxide radical in the impaired endothelium-dependent relaxation of cavernous smooth muscle in hypercholesterolemic rabbits. Urol. Res. 1997, 25, 341–346. [Google Scholar] [CrossRef]
- Kaltsas, A. Oxidative Stress and Male Infertility: The Protective Role of Antioxidants. Medicina 2023, 59, 1769. [Google Scholar] [CrossRef] [PubMed]
- Zhou, B.; Chen, Y.; Yuan, H.; Wang, T.; Feng, J.; Li, M.; Liu, J. NOX1/4 Inhibitor GKT-137831 Improves Erectile Function in Diabetic Rats by ROS Reduction and Endothelial Nitric Oxide Synthase Reconstitution. J. Sex. Med. 2021, 18, 1970–1983. [Google Scholar] [CrossRef]
- Tostes, R.C.; Carneiro, F.S.; Lee, A.J.; Giachini, F.R.; Leite, R.; Osawa, Y.; Webb, R.C. Cigarette smoking and erectile dysfunction: Focus on NO bioavailability and ROS generation. J. Sex. Med. 2008, 5, 1284–1295. [Google Scholar] [CrossRef]
- Paulis, G.; De Giorgio, G. Full Regression of Peyronie’s Disease Plaque Following Combined Antioxidant Treatment: A Three-Case Report. Antioxidants 2022, 11, 1661. [Google Scholar] [CrossRef]
- Fraga-Silva, R.A.; Costa-Fraga, F.P.; Savergnini, S.Q.; De Sousa, F.B.; Montecucco, F.; da Silva, D.; Sinisterra, R.D.; Mach, F.; Stergiopulos, N.; da Silva, R.F.; et al. An oral formulation of angiotensin-(1-7) reverses corpus cavernosum damages induced by hypercholesterolemia. J. Sex. Med. 2013, 10, 2430–2442. [Google Scholar] [CrossRef] [PubMed]
- La Favor, J.D.; Rhein, P.J.; Pierre, C.J.; Azeez, T.; Burnett, A.L. (090) Hydrogen Sulfide Therapy Stimulates Cellular Antioxidant Defense and Reverses Erectile Dysfunction in Western Diet-fed Mice. J. Sex. Med. 2023, 20, qdad060.085. [Google Scholar] [CrossRef]
- Sheweita, S.A.; Meftah, A.A.; Sheweita, M.S.; Balbaa, M.E. Erectile dysfunction drugs altered the activities of antioxidant enzymes, oxidative stress and the protein expressions of some cytochrome P450 isozymes involved in the steroidogenesis of steroid hormones. PLoS ONE 2020, 15, e0241509. [Google Scholar] [CrossRef]
- Fu, H.; Bai, X.; Le, L.; Tian, D.; Gao, H.; Qi, L.X.; Hu, K.P. Eucommia ulmoides Oliv. Leaf Extract Improves Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats by Protecting Endothelial Function and Ameliorating Hypothalamic-Pituitary-Gonadal Axis Function. Evid. Based Complement. Alternat Med. 2019, 2019, 1782953. [Google Scholar] [CrossRef] [PubMed]
- Jeffrey, S.; Samraj, P.I.; Raj, B.S. The Role of Alpha-lipoic Acid Supplementation in the Prevention of Diabetes Complications: A Comprehensive Review of Clinical Trials. Curr. Diabetes Rev. 2021, 17, e011821190404. [Google Scholar] [CrossRef] [PubMed]
- Tadayon Najafabadi, B.; Jafarinia, M.; Ghamari, K.; Shokraee, K.; Tadayyon, F.; Akhondzadeh, S. Vitamin E and ginseng combined supplement for treatment of male erectile dysfunction: A double-blind, placebo-controlled, randomized, clinical trial. Adv. Integr. Med. 2019, 8, 44–49. [Google Scholar] [CrossRef]
- Tang, Z.; Song, J.; Yu, Z.; Cui, K.; Ruan, Y.; Wang, T.; Yang, J.; Wang, S.; Liu, J. Melatonin Treatment Ameliorates Hyperhomocysteinemia-Induced Impairment of Erectile Function in a Rat Model. J. Sex. Med. 2019, 16, 1506–1517. [Google Scholar] [CrossRef] [PubMed]
- Shivavedi, N.; Charan Tej, G.N.V.; Neogi, K.; Nayak, P.K. Ascorbic acid therapy: A potential strategy against comorbid depression-like behavior in streptozotocin-nicotinamide-induced diabetic rats. Biomed. Pharmacother. 2019, 109, 351–359. [Google Scholar] [CrossRef] [PubMed]
- Wang, W.; Kang, P.M. Oxidative Stress and Antioxidant Treatments in Cardiovascular Diseases. Antioxidants 2020, 9, 1292. [Google Scholar] [CrossRef]
- Song, J.; Tang, Z.; Li, H.; Jiang, H.; Sun, T.; Lan, R.; Wang, T.; Wang, S.; Ye, Z.; Liu, J. Role of JAK2 in the Pathogenesis of Diabetic Erectile Dysfunction and an Intervention With Berberine. J. Sex. Med. 2019, 16, 1708–1720. [Google Scholar] [CrossRef] [PubMed]
- Madeira, C.R.; Tonin, F.S.; Fachi, M.M.; Borba, H.H.; Ferreira, V.L.; Leonart, L.P.; Bonetti, A.F.; Moritz, R.P.; Trindade, A.C.L.B.; Goncalves, A.G.; et al. Efficacy and safety of oral phosphodiesterase 5 inhibitors for erectile dysfunction: A network meta-analysis and multicriteria decision analysis. World J. Urol. 2021, 39, 953–962. [Google Scholar] [CrossRef] [PubMed]
- Sofikitis, N.; Kaltsas, A.; Dimitriadis, F.; Rassweiler, J.; Grivas, N.; Zachariou, A.; Kaponis, A.; Tsounapi, P.; Paterakis, N.; Karagiannis, A.; et al. The Effect of PDE5 Inhibitors on the Male Reproductive Tract. Curr. Pharm. Des. 2021, 27, 2697–2713. [Google Scholar] [CrossRef] [PubMed]
- Dimitriadis, F.; Kaltsas, A.; Zachariou, A.; Mamoulakis, C.; Tsiampali, C.; Giannakis, I.; Paschopoulos, M.; Papatsoris, A.; Loutradis, D.; Tsounapi, P.; et al. PDE5 inhibitors and male reproduction: Is there a place for PDE5 inhibitors in infertility clinics or andrology laboratories? Int. J. Urol. 2022, 29, 1405–1418. [Google Scholar] [CrossRef]
- Pyrgidis, N.; Mykoniatis, I.; Haidich, A.B.; Tirta, M.; Talimtzi, P.; Kalyvianakis, D.; Ouranidis, A.; Hatzichristou, D. Effect of phosphodiesterase-type 5 inhibitors on erectile function: An overview of systematic reviews and meta-analyses. BMJ Open 2021, 11, e047396. [Google Scholar] [CrossRef] [PubMed]
- Bivalacqua, T.J.; Sussan, T.E.; Gebska, M.A.; Strong, T.D.; Berkowitz, D.E.; Biswal, S.; Burnett, A.L.; Champion, H.C. Sildenafil inhibits superoxide formation and prevents endothelial dysfunction in a mouse model of secondhand smoke induced erectile dysfunction. J. Urol. 2009, 181, 899–906. [Google Scholar] [CrossRef] [PubMed]
- Hotston, M.; Jeremy, J.Y.; Bloor, J.; Greaves, N.S.; Persad, R.; Angelini, G.; Shukla, N. Homocysteine and copper interact to promote type 5 phosphodiesterase expression in rabbit cavernosal smooth muscle cells. Asian J. Androl. 2008, 10, 905–913. [Google Scholar] [CrossRef] [PubMed]
- Koupparis, A.J.; Jeremy, J.Y.; Muzaffar, S.; Persad, R.; Shukla, N. Sildenafil inhibits the formation of superoxide and the expression of gp47phox NAD[P]H oxidase induced by the thromboxane A2 mimetic, U46619, in corpus cavernosal smooth muscle cells. BJU Int. 2005, 96, 423–427. [Google Scholar] [CrossRef]
- Tzoumas, N.; Farrah, T.E.; Dhaun, N.; Webb, D.J. Established and emerging therapeutic uses of PDE type 5 inhibitors in cardiovascular disease. Br. J. Pharmacol. 2020, 177, 5467–5488. [Google Scholar] [CrossRef] [PubMed]
- Shukla, N.; Rossoni, G.; Hotston, M.; Sparatore, A.; Del Soldato, P.; Tazzari, V.; Persad, R.; Angelini, G.D.; Jeremy, J.Y. Effect of hydrogen sulphide-donating sildenafil (ACS6) on erectile function and oxidative stress in rabbit isolated corpus cavernosum and in hypertensive rats. BJU Int. 2009, 103, 1522–1529. [Google Scholar] [CrossRef] [PubMed]
- Saikia, Q.; Hazarika, A.K.; Mishra, R. A Review on the Pharmacological Importance of PDE5 and Its Inhibition to Manage Biomedical Conditions. J. Pharmacol. Pharmacother. 2022, 13, 246–257. [Google Scholar] [CrossRef]
- Barbagallo, F.; Campolo, F.; Franceschini, E.; Crecca, E.; Pofi, R.; Isidori, A.M.; Venneri, M.A. PDE5 Inhibitors in Type 2 Diabetes Cardiovascular Complications. Endocrines 2020, 1, 90–101. [Google Scholar] [CrossRef]
- Verit, A.; Savas, M.; Ciftci, H.; Aksoy, N.; Taskin, A.; Topal, U. Assessment of the acute effects of tadalafil on the cardiovascular system based on examination of serum oxidative status and paraoxonase activity in men with erectile dysfunction: A preliminary study. Int. J. Impot. Res. 2010, 22, 115–119. [Google Scholar] [CrossRef]
- Lombardo, R.; Tema, G.; De Nunzio, C. Phosphodiesterases 5 Inhibitors and Erectile Dysfunction Recovery after Pelvic Surgery: Future Perspectives for New Drugs and New Formulations. Curr. Drug Targets 2021, 22, 31–37. [Google Scholar] [CrossRef]
- Deger, M.D.; Madendere, S. Erectile dysfunction treatment with Phosphodiesterase-5 Inhibitors: Google trends analysis of last 10 years and COVID-19 pandemic. Arch. Ital. Urol. Androl. 2021, 93, 361–365. [Google Scholar] [CrossRef] [PubMed]
- Ding, J.; Yu, M.; Jiang, J.; Luo, Y.; Zhang, Q.; Wang, S.; Yang, F.; Wang, A.; Wang, L.; Zhuang, M.; et al. Angiotensin II Decreases Endothelial Nitric Oxide Synthase Phosphorylation via AT(1)R Nox/ROS/PP2A Pathway. Front. Physiol. 2020, 11, 566410. [Google Scholar] [CrossRef] [PubMed]
- Friedrich, E.B.; Teo, K.K.; Bohm, M. ACE inhibition in secondary prevention: Are the results controversial? Clin. Res. Cardiol. 2006, 95, 61–67. [Google Scholar] [CrossRef]
- do Vale, G.T.; Tirapelli, C.R. Are Reactive Oxygen Species Important Mediators of Vascular Dysfunction? Curr. Hypertens. Rev. 2020, 16, 163–165. [Google Scholar] [CrossRef] [PubMed]
- Nunes, K.P.; Labazi, H.; Webb, R.C. New insights into hypertension-associated erectile dysfunction. Curr. Opin. Nephrol. Hypertens. 2012, 21, 163–170. [Google Scholar] [CrossRef] [PubMed]
- Baumhakel, M.; Custodis, F.; Schlimmer, N.; Laufs, U.; Bohm, M. Improvement of endothelial function of the corpus cavernosum in apolipoprotein E knockout mice treated with irbesartan. J. Pharmacol. Exp. Ther. 2008, 327, 692–698. [Google Scholar] [CrossRef]
- Park, K.; Shin, J.W.; Oh, J.K.; Ryu, K.S.; Kim, S.W.; Paick, J.S. Restoration of erectile capacity in normotensive aged rats by modulation of angiotensin receptor type 1. J. Androl. 2005, 26, 123–128. [Google Scholar] [CrossRef] [PubMed]
- Idris Khodja, N.; Chataigneau, T.; Auger, C.; Schini-Kerth, V.B. Grape-derived polyphenols improve aging-related endothelial dysfunction in rat mesenteric artery: Role of oxidative stress and the angiotensin system. PLoS ONE 2012, 7, e32039. [Google Scholar] [CrossRef]
- Chen, F.P.; Gong, L.K.; Zhang, L.; Wang, H.; Qi, X.M.; Wu, X.F.; Xiao, Y.; Cai, Y.; Liu, L.L.; Li, X.H.; et al. Early lung injury contributes to lung fibrosis via AT1 receptor in rats. Acta Pharmacol. Sin. 2007, 28, 227–237. [Google Scholar] [CrossRef]
- Yanagitani, Y.; Rakugi, H.; Okamura, A.; Moriguchi, K.; Takiuchi, S.; Ohishi, M.; Suzuki, K.; Higaki, J.; Ogihara, T. Angiotensin II type 1 receptor-mediated peroxide production in human macrophages. Hypertension 1999, 33, 335–339. [Google Scholar] [CrossRef]
- Zinellu, A.; Mangoni, A.A. A Systematic Review and Meta-Analysis of the Effect of Statins on Glutathione Peroxidase, Superoxide Dismutase, and Catalase. Antioxidants 2021, 10, 1841. [Google Scholar] [CrossRef]
- Adam, O.; Laufs, U. Antioxidative effects of statins. Arch. Toxicol. 2008, 82, 885–892. [Google Scholar] [CrossRef]
- Wassmann, S.; Laufs, U.; Baumer, A.T.; Muller, K.; Ahlbory, K.; Linz, W.; Itter, G.; Rosen, R.; Bohm, M.; Nickenig, G. HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension 2001, 37, 1450–1457. [Google Scholar] [CrossRef]
- Wenzel, P.; Daiber, A.; Oelze, M.; Brandt, M.; Closs, E.; Xu, J.; Thum, T.; Bauersachs, J.; Ertl, G.; Zou, M.H.; et al. Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus. Atherosclerosis 2008, 198, 65–76. [Google Scholar] [CrossRef]
- Park, B.H.; Han, D.-S.; Yuk, S.M.; Youn, C.S.; Kwon, E.B.; Park, K.C.; Jang, H. Preservation of erectile function by statins in a rat model of erectile dysfunction induced by hypercholesterolemia. J. Men’s Health 2020, 16, 27–40. [Google Scholar]
- Miner, M.; Billups, K.L. Erectile dysfunction and dyslipidemia: Relevance and role of phosphodiesterase type-5 inhibitors and statins. J. Sex. Med. 2008, 5, 1066–1078. [Google Scholar] [CrossRef] [PubMed]
- Hong, S.K.; Han, B.K.; Jeong, S.J.; Byun, S.S.; Lee, S.E. Effect of statin therapy on early return of potency after nerve sparing radical retropubic prostatectomy. J. Urol. 2007, 178, 613–616. [Google Scholar] [CrossRef] [PubMed]
- La Vignera, S.; Condorelli, R.A.; Vicari, E.; Calogero, A.E. Statins and erectile dysfunction: A critical summary of current evidence. J. Androl. 2012, 33, 552–558. [Google Scholar] [CrossRef]
- Rizvi, K.; Hampson, J.P.; Harvey, J.N. Do lipid-lowering drugs cause erectile dysfunction? A systematic review. Fam. Pract. 2002, 19, 95–98. [Google Scholar] [CrossRef]
- Solomon, H.; Samarasinghe, Y.P.; Feher, M.D.; Man, J.; Rivas-Toro, H.; Lumb, P.J.; Wierzbicki, A.S.; Jackson, G. Erectile dysfunction and statin treatment in high cardiovascular risk patients. Int. J. Clin. Pract. 2006, 60, 141–145. [Google Scholar] [CrossRef]
- Bendall, J.K.; Douglas, G.; McNeill, E.; Channon, K.M.; Crabtree, M.J. Tetrahydrobiopterin in cardiovascular health and disease. Antioxid. Redox Signal. 2014, 20, 3040–3077. [Google Scholar] [CrossRef] [PubMed]
- Chuaiphichai, S.; Chu, S.M.; Carnicer, R.; Kelly, M.; Bendall, J.K.; Simon, J.N.; Douglas, G.; Crabtree, M.J.; Casadei, B.; Channon, K.M. Endothelial cell-specific roles for tetrahydrobiopterin in myocardial function, cardiac hypertrophy, and response to myocardial ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 2023, 324, H430–H442. [Google Scholar] [CrossRef] [PubMed]
- Chen, D.D.; Chen, L.Y.; Xie, J.B.; Shu, C.; Yang, T.; Zhou, S.; Yuan, H.; Chen, A.F. Tetrahydrobiopterin regulation of eNOS redox function. Curr. Pharm. Des. 2014, 20, 3554–3562. [Google Scholar] [CrossRef] [PubMed]
- Rudrapal, M.; Khairnar, S.J.; Khan, J.; Dukhyil, A.B.; Ansari, M.A.; Alomary, M.N.; Alshabrmi, F.M.; Palai, S.; Deb, P.K.; Devi, R. Dietary Polyphenols and Their Role in Oxidative Stress-Induced Human Diseases: Insights Into Protective Effects, Antioxidant Potentials and Mechanism(s) of Action. Front. Pharmacol. 2022, 13, 806470. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Q.; Radisavljevic, Z.M.; Siroky, M.B.; Azadzoi, K.M. Dietary antioxidants improve arteriogenic erectile dysfunction. Int. J. Androl. 2011, 34, 225–235. [Google Scholar] [CrossRef] [PubMed]
- Azadzoi, K.M.; Schulman, R.N.; Aviram, M.; Siroky, M.B. Oxidative stress in arteriogenic erectile dysfunction: Prophylactic role of antioxidants. J. Urol. 2005, 174, 386–393. [Google Scholar] [CrossRef]
- Zarfeshany, A.; Asgary, S.; Javanmard, S.H. Potent health effects of pomegranate. Adv. Biomed. Res. 2014, 3, 100. [Google Scholar] [CrossRef]
- Weiskirchen, S.; Weiskirchen, R. Resveratrol: How Much Wine Do You Have to Drink to Stay Healthy? Adv. Nutr. 2016, 7, 706–718. [Google Scholar] [CrossRef] [PubMed]
- Lasker, G.F.; Pankey, E.A.; Kadowitz, P.J. Modulation of soluble guanylate cyclase for the treatment of erectile dysfunction. Physiology 2013, 28, 262–269. [Google Scholar] [CrossRef]
- Allen, M.S.; Wood, A.M.; Sheffield, D. The Psychology of Erectile Dysfunction. Curr. Dir. Psychol. Sci. 2023, 32, 487–493. [Google Scholar] [CrossRef]
ROS-Generating Sources | Function and Mechanism | Conditions | Clinical and Experimental Models |
---|---|---|---|
NADPH oxidase | - Generates ROS by transferring electrons from NADPH to O₂ [54] - Comprises cytosolic (p47phox, p67phox) and membrane (p22phox, gp91phox) components [55,56] | Diabetes Mellitus, Hypertension, Cigarette Smoking, Sickle Cell Disease, Hyperhomocysteinemia, Obesity, Psychological Stress [57] | - Diabetes (rats) [114,117,118], - Hypertension (rats) [123,124], - Smoking (mice) [142,143], - Sickle Cell Disease (mice) [172], - Hyperhomocysteinemia (rabbits) [164,165], - Psychological Stress (rats) [161], - Obesity (human) [88] |
eNOS uncoupling | - NOS isoforms (eNOS, nNOS, iNOS) typically produce NO - Under pathological conditions, produce superoxide (uncoupling) [67] | Aging, Diabetes Mellitus, Hyperlipidemia, Sickle Cell Disease, Cigarette Smoking, Chronic Kidney Disease [75] | - Aging (rats) [90], - Diabetes (mice) [112,113], - Hyperlipidemia (mice) [129,130], - SCD (mice) [172], - Obesity (human) [88], - Smoking (mice) [142,143], - Chronic Kidney Disease (mice) [135] |
Mitochondrial ROS | - Produced during oxidative phosphorylation [79] - ETC in inner mitochondrial membrane transfers electrons through complexes I–IV [80] | Diabetes Mellitus, Hyperlipidemia [84] | - Diabetes Mellitus (mice) [84] - Hyperlipidemia (rats) [134] |
Xanthine oxidase | - Converts hypoxanthine to xanthine, then uric acid - Generates ROS (hydrogen peroxide, superoxides) [60,61] | Diabetes Mellitus, Hyperlipidemia, Sickle Cell Disease [64] | - Diabetes (rats) [64], - Hyperlipidemia (rats) [134], - Sickle Cell Disease (mice) [172] |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Kaltsas, A.; Zikopoulos, A.; Dimitriadis, F.; Sheshi, D.; Politis, M.; Moustakli, E.; Symeonidis, E.N.; Chrisofos, M.; Sofikitis, N.; Zachariou, A. Oxidative Stress and Erectile Dysfunction: Pathophysiology, Impacts, and Potential Treatments. Curr. Issues Mol. Biol. 2024, 46, 8807-8834. https://doi.org/10.3390/cimb46080521
Kaltsas A, Zikopoulos A, Dimitriadis F, Sheshi D, Politis M, Moustakli E, Symeonidis EN, Chrisofos M, Sofikitis N, Zachariou A. Oxidative Stress and Erectile Dysfunction: Pathophysiology, Impacts, and Potential Treatments. Current Issues in Molecular Biology. 2024; 46(8):8807-8834. https://doi.org/10.3390/cimb46080521
Chicago/Turabian StyleKaltsas, Aris, Athanasios Zikopoulos, Fotios Dimitriadis, Danja Sheshi, Magdalena Politis, Efthalia Moustakli, Evangelos N. Symeonidis, Michael Chrisofos, Nikolaos Sofikitis, and Athanasios Zachariou. 2024. "Oxidative Stress and Erectile Dysfunction: Pathophysiology, Impacts, and Potential Treatments" Current Issues in Molecular Biology 46, no. 8: 8807-8834. https://doi.org/10.3390/cimb46080521