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Oxidative Stress in Vascular Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 August 2017) | Viewed by 70033

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Prof. Dr. Neal Weintraub

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Medical College of Georgia, Augusta University, Augusta, GA, USA
Interests: cardiovascular disease; metabolic disease; cardio-oncology; epigenetics; inflammation; oxidative stress; vascular biology; lipid metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oxidative stress, broadly defined as tissue damage resulting from an imbalance between the production and degradation of reactive oxygen species (ROS), is prominent in many vascular diseases and has been implicated in the pathogenesis of diverse conditions including atherosclerosis, neointimal hyperplasia, and abdominal aortic aneurysms (AAA). Pathologically, oxidative stress disrupts physiologic nitric oxide signaling while promoting vascular inflammation, lipid accumulation, apoptosis, protease-mediated degradation of the extracellular matrix, etc. Vascular oxidative stress can be triggered by activation of specific oxidant-generating enzymes and/or by disruption of endogenous antioxidant defense mechanisms. The overall goal of this thematic issue is to (i) summarize evidence that mechanistically links oxidative stress to vascular diseases such as AAA, with a particular emphasis on human studies; (ii) provide data supporting the role of specific oxidant-generating enzymatic pathways, such as NADPH oxidase, in vascular diseases; (iii) demonstrate the role of key antioxidant defense pathways in mitigating vascular disease; and (iv) exhibit the potential benefit of targeting oxidative stress as a biomarker and treatment strategy for vascular diseases.

Prof. Dr. Neal Weintraub
Guest Editor

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Keywords

Atherosclerosis
Abdominal aortic aneurysm
Neointima
Inflammation
Oxidative stress
Matrix metalloproteinase
Reactive oxygen species
NADPH oxidase
Antioxidant
Superoxide dismutase

Published Papers (10 papers)

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3121 KiB

Open AccessArticle

APE1/Ref-1 Inhibits Phosphate-Induced Calcification and Osteoblastic Phenotype Changes in Vascular Smooth Muscle Cells

by Ki Mo Lee, Eun Ok Lee, Yu Ran Lee, Hee Kyoung Joo, Myoung Soo Park, Cuk-Seong Kim, Sunga Choi, Jin-Ok Jeong and Byeong Hwa Jeon

Int. J. Mol. Sci. 2017, 18(10), 2053; https://doi.org/10.3390/ijms18102053 - 25 Sep 2017

Cited by 19 | Viewed by 7997

Abstract

Vascular calcification plays a role in the pathogenesis of atherosclerosis, diabetes, and chronic kidney disease; however, the role of apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) in inorganic phosphate (Pi)-induced vascular smooth muscle cell (VSMC) calcification remains unknown. In this study, we investigated the possible role of APE1/Ref-1 in Pi-induced VSMC calcification. We observed that Pi decreased endogenous APE1/Ref-1 expression and promoter activity in VSMCs, and that adenoviral overexpression of APE1/Ref-1 inhibited Pi-induced calcification in VSMCs and in an ex vivo organ culture of a rat aorta. However, a redox mutant of APE1/Ref-1(C65A/C93A) did not reduce Pi-induced calcification in VSMCs, suggesting APE1/Ref-1-mediated redox function against vascular calcification. Additionally, APE1/Ref-1 overexpression inhibited Pi-induced intracellular and mitochondrial reactive oxygen species production, and APE1/Ref-1 overexpression resulted in decreased Pi-induced lactate dehydrogenase activity, pro-apoptotic Bax levels, and increased anti-apoptotic Bcl-2 protein levels. Furthermore, APE1/Ref-1 inhibited Pi-induced osteoblastic differentiation associated with alkaline phosphatase activity and inhibited Pi-exposure-induced loss of the smooth muscle phenotype. Our findings provided valuable insights into the redox function of APE1/Ref-1 in preventing Pi-induced VSMC calcification by inhibiting oxidative stress and osteoblastic differentiation, resulting in prevention of altered osteoblastic phenotypes in VSMCs. Full article

(This article belongs to the Special Issue Oxidative Stress in Vascular Diseases)

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by Haijian Sun, Xuexue Zhu, Yuetao Zhou, Weiwei Cai and Liying Qiu

Int. J. Mol. Sci. 2017, 18(6), 1097; https://doi.org/10.3390/ijms18061097 - 26 May 2017

Cited by 42 | Viewed by 8766

Abstract

Oxidized low-density lipoprotein (ox-LDL) accumulation is one of the critical determinants in endothelial dysfunction in many cardiovascular diseases such as atherosclerosis. C1q/TNF-related protein 9 (CTRP9) is identified to be an adipocytokine with cardioprotective properties. However, the potential roles of CTRP9 in endothelial function remain largely elusive. In the present study, the effects of CTRP9 on the proliferation, apoptosis, migration, angiogenesis, nitric oxide (NO) production and oxidative stress in human umbilical vein endothelial cells (HUVECs) exposed to ox-LDL were investigated. We observed that treatment with ox-LDL inhibited the proliferation, migration, angiogenesis and the generation of NO, while stimulated the apoptosis and reactive oxygen species (ROS) production in HUVECs. Incubation of HUVECs with CTRP9 rescued ox-LDL-induced endothelial injury. CTRP9 treatment reversed ox-LDL-evoked decreases in antioxidant enzymes including heme oxygenase-1 (HO-1), nicotinamide adenine dinucleotide phosphate (NAD(P)H) dehydrogenase quinone 1, and glutamate-cysteine ligase (GCL), as well as endothelial nitric oxide synthase (eNOS). Furthermore, CTRP9 induced activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC1-α) and phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Of interest, AMPK inhibition or PGC1-α silencing abolished CTRP9-mediated antioxidant enzymes levels, eNOS expressions, and endothelial protective effects. Collectively, we provided the first evidence that CTRP9 attenuated ox-LDL-induced endothelial injury by antioxidant enzyme inductions dependent on PGC-1α/AMPK activation. Full article

(This article belongs to the Special Issue Oxidative Stress in Vascular Diseases)

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Open AccessArticle

Galectin-3 in Peripheral Artery Disease. Relationships with Markers of Oxidative Stress and Inflammation

by Isabel Fort-Gallifa, Anna Hernández-Aguilera, Anabel García-Heredia, Noemí Cabré, Fedra Luciano-Mateo, Josep M. Simó, Vicente Martín-Paredero, Jordi Camps and Jorge Joven

Int. J. Mol. Sci. 2017, 18(5), 973; https://doi.org/10.3390/ijms18050973 - 04 May 2017

Cited by 32 | Viewed by 4465

Abstract

Galectin-3 is a modulator of oxidative stress, inflammation, and fibrogenesis involved in the pathogenesis of vascular diseases. The present study sought to characterize, in patients with peripheral artery disease (PAD), the localization of galectin-3 in arterial tissue, and to analyze the relationships between the circulating levels of galectin-3 and oxidative stress and inflammation. It also sought to compare the diagnostic accuracy of galectin-3 with that of other biochemical markers of this disease. We analyzed femoral or popliteal arteries from 50 PAD patients, and four control arteries. Plasma from 86 patients was compared with that from 72 control subjects. We observed differences in the expression of galectin-3 in normal arteries, and arteries from patients with PAD, with a displacement of the expression from the adventitia to the media, and the intima. In addition, plasma galectin-3 concentration was increased in PAD patients, and correlated with serologic markers of oxidative stress (F2-isoprostanes), and inflammation [chemokine (C−C motif) ligand 2, C-reactive protein, β-2-microglobulin]. We conclude that the determination of galectin-3 has good diagnostic accuracy in the assessment of PAD and compares well with other analytical parameters currently in use. Full article

(This article belongs to the Special Issue Oxidative Stress in Vascular Diseases)

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Review

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1178 KiB

Open AccessReview

Cellular and Oxidative Mechanisms Associated with Interleukin-6 Signaling in the Vasculature

by Sean P. Didion

Int. J. Mol. Sci. 2017, 18(12), 2563; https://doi.org/10.3390/ijms18122563 - 29 Nov 2017

Cited by 125 | Viewed by 9859

Abstract

Reactive oxygen species, particularly superoxide, promote endothelial dysfunction and alterations in vascular structure. It is increasingly recognized that inflammatory cytokines, such as interleukin-6 (IL-6), contribute to endothelial dysfunction and vascular hypertrophy and fibrosis. IL-6 is increased in a number of cardiovascular diseases, including hypertension. IL-6 is also associated with a higher incidence of future cardiovascular events and all-cause mortality. Both immune and vascular cells produce IL-6 in response to a number of stimuli, such as angiotensin II. The vasculature is responsive to IL-6 produced from vascular and non-vascular sources via classical IL-6 signaling involving a membrane-bound IL-6 receptor (IL-6R) and membrane-bound gp130 via Jak/STAT as well as SHP2-dependent signaling pathways. IL-6 signaling is unique because it can also occur via a soluble IL-6 receptor (sIL-6R) which allows for IL-6 signaling in tissues that do not normally express IL-6R through a process referred to as IL-6 trans-signaling. IL-6 signaling mediates a vast array of effects in the vascular wall, including endothelial activation, vascular permeability, immune cell recruitment, endothelial dysfunction, as well as vascular hypertrophy and fibrosis. Many of the effects of IL-6 on vascular function and structure are representative of loss or reductions in nitric oxide (NO) bioavailability. IL-6 has direct effects on endothelial nitric oxide synthase activity and expression as well as increasing vascular superoxide, which rapidly inactivates NO thereby limiting NO bioavailability. The goal of this review is to highlight both the cellular and oxidative mechanisms associated with IL-6-signaling in the vascular wall in general, in hypertension, and in response to angiotensin II. Full article

(This article belongs to the Special Issue Oxidative Stress in Vascular Diseases)

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573 KiB

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A Mini-Review of the NADPH Oxidases in Vascular Dementia: Correlation with NOXs and Risk Factors for VaD

by Dong-Hee Choi and Jongmin Lee

Int. J. Mol. Sci. 2017, 18(11), 2500; https://doi.org/10.3390/ijms18112500 - 22 Nov 2017

Cited by 24 | Viewed by 6602

Abstract

Oxidative stress (OS) is one of the factors that cause dementia conditions such as Alzheimer’s disease and vascular dementia (VaD). In the pathogenesis of VaD, OS is associated with risk factors that include increased age, hypertension, and stroke. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are a molecular source of reactive oxygen species (ROS). According to recent studies, inhibition of NOX activity can reduce cognitive impairment in animal models of VaD. In this article, we review the evidence linking cognitive impairment with NOX-dependent OS, including the vascular NOX and non-vascular NOX systems, in VaD. Full article

(This article belongs to the Special Issue Oxidative Stress in Vascular Diseases)

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Infectious Agents in Atherosclerotic Cardiovascular Diseases through Oxidative Stress

by Marisa Di Pietro, Simone Filardo, Francesca Falasca, Ombretta Turriziani and Rosa Sessa

Int. J. Mol. Sci. 2017, 18(11), 2459; https://doi.org/10.3390/ijms18112459 - 18 Nov 2017

Cited by 44 | Viewed by 6561

Abstract

Accumulating evidence demonstrates that vascular oxidative stress is a critical feature of atherosclerotic process, potentially triggered by several infectious agents that are considered as risk co-factors for the atherosclerotic cardiovascular diseases (CVDs). C. pneumoniae has been shown to upregulate multiple enzymatic systems capable of producing reactive oxygen species (ROS) such as NADPH oxidase (NOX) and cyclooxygenase in vascular endothelial cells, NOX and cytochrome c oxidase in macrophages as well as nitric oxide synthase and lipoxygenase in platelets contributing to both early and late stages of atherosclerosis. P. gingivalis seems to be markedly involved in the atherosclerotic process as compared to A. actinomycetemcomitans contributing to LDL oxidation and foam cell formation. Particularly interesting is the evidence describing the NLRP3 inflammasome activation as a new molecular mechanism underlying P. gingivalis-induced oxidative stress and inflammation. Amongst viral agents, immunodeficiency virus-1 and hepatitis C virus seem to have a major role in promoting ROS production, contributing, hence, to the early stages of atherosclerosis including endothelial dysfunction and LDL oxidation. In conclusion, oxidative mechanisms activated by several infectious agents during the atherosclerotic process underlying CVDs are very complex and not well-known, remaining, thus, an attractive target for future research. Full article

(This article belongs to the Special Issue Oxidative Stress in Vascular Diseases)

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Oxidative Stress in Human Atherothrombosis: Sources, Markers and Therapeutic Targets

by Jose Luis Martin-Ventura, Raquel Rodrigues-Diez, Diego Martinez-Lopez, Mercedes Salaices, Luis Miguel Blanco-Colio and Ana M. Briones

Int. J. Mol. Sci. 2017, 18(11), 2315; https://doi.org/10.3390/ijms18112315 - 03 Nov 2017

Cited by 47 | Viewed by 5907

Abstract

Atherothrombosis remains one of the main causes of morbidity and mortality worldwide. The underlying pathology is a chronic pathological vascular remodeling of the arterial wall involving several pathways, including oxidative stress. Cellular and animal studies have provided compelling evidence of the direct role of oxidative stress in atherothrombosis, but such a relationship is not clearly established in humans and, to date, clinical trials on the possible beneficial effects of antioxidant therapy have provided equivocal results. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is one of the main sources of reactive oxygen species (ROS) in human atherothrombosis. Moreover, leukocyte-derived myeloperoxidase (MPO) and red blood cell-derived iron could be involved in the oxidative modification of lipids/lipoproteins (LDL/HDL) in the arterial wall. Interestingly, oxidized lipoproteins, and antioxidants, have been analyzed as potential markers of oxidative stress in the plasma of patients with atherothrombosis. In this review, we will revise sources of ROS, focusing on NADPH oxidase, but also on MPO and iron. We will also discuss the impact of these oxidative systems on LDL and HDL, as well as the value of these modified lipoproteins as circulating markers of oxidative stress in atherothrombosis. We will finish by reviewing some antioxidant systems and compounds as therapeutic strategies to prevent pathological vascular remodeling. Full article

(This article belongs to the Special Issue Oxidative Stress in Vascular Diseases)

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A Mini-Review of Reactive Oxygen Species in Urological Cancer: Correlation with NADPH Oxidases, Angiogenesis, and Apoptosis

by Yasuyoshi Miyata, Tomohiro Matsuo, Yuji Sagara, Kojiro Ohba, Kaname Ohyama and Hideki Sakai

Int. J. Mol. Sci. 2017, 18(10), 2214; https://doi.org/10.3390/ijms18102214 - 22 Oct 2017

Cited by 45 | Viewed by 7006

Abstract

Oxidative stress refers to elevated reactive oxygen species (ROS) levels, and NADPH oxidases (NOXs), which are one of the most important sources of ROS. Oxidative stress plays important roles in the etiologies, pathological mechanisms, and treatment strategies of vascular diseases. Additionally, oxidative stress affects mechanisms of carcinogenesis, tumor growth, and prognosis in malignancies. Nearly all solid tumors show stimulation of neo-vascularity, termed angiogenesis, which is closely associated with malignant aggressiveness. Thus, cancers can be seen as a type of vascular disease. Oxidative stress-induced functions are regulated by complex endogenous mechanisms and exogenous factors, such as medication and diet. Although understanding these regulatory mechanisms is important for improving the prognosis of urothelial cancer, it is not sufficient, because there are controversial and conflicting opinions. Therefore, we believe that this knowledge is essential to discuss observations and treatment strategies in urothelial cancer. In this review, we describe the relationships between members of the NOX family and tumorigenesis, tumor growth, and pathological mechanisms in urological cancers including prostate cancer, renal cell carcinoma, and urothelial cancer. In addition, we introduce natural compounds and chemical agents that are associated with ROS-induced angiogenesis or apoptosis. Full article

(This article belongs to the Special Issue Oxidative Stress in Vascular Diseases)

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NADPH Oxidase-Related Pathophysiology in Experimental Models of Stroke

by Hiroshi Yao, Tetsuro Ago, Takanari Kitazono and Toru Nabika

Int. J. Mol. Sci. 2017, 18(10), 2123; https://doi.org/10.3390/ijms18102123 - 11 Oct 2017

Cited by 23 | Viewed by 5665

Abstract

Several experimental studies have indicated that nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) exert detrimental effects on ischemic brain tissue; Nox-knockout mice generally exhibit resistance to damage due to experimental stroke following middle cerebral artery occlusion (MCAO). Furthermore, our previous MCAO study indicated that infarct size and blood-brain barrier breakdown are enhanced in mice with pericyte-specific overexpression of Nox4, relative to levels observed in controls. However, it remains unclear whether Nox affects the stroke outcome directly by increasing oxidative stress at the site of ischemia, or indirectly by modifying physiological variables such as blood pressure or cerebral blood flow (CBF). Because of technical problems in the measurement of physiological variables and CBF, it is often difficult to address this issue in mouse models due to their small body size; in our previous study, we examined the effects of Nox activity on focal ischemic injury in a novel congenic rat strain: stroke-prone spontaneously hypertensive rats with loss-of-function in Nox. In this review, we summarize the current literature regarding the role of Nox in focal ischemic injury and discuss critical issues that should be considered when investigating Nox-related pathophysiology in animal models of stroke. Full article

(This article belongs to the Special Issue Oxidative Stress in Vascular Diseases)

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The Future Challenge of Reactive Oxygen Species (ROS) in Hypertension: From Bench to Bed Side

by Gabriele Togliatto, Giusy Lombardo and Maria Felice Brizzi

Int. J. Mol. Sci. 2017, 18(9), 1988; https://doi.org/10.3390/ijms18091988 - 15 Sep 2017

Cited by 72 | Viewed by 6478

Abstract

Reactive oxygen species (ROS) act as signaling molecules that control physiological processes, including cell adaptation to stress. Redox signaling via ROS has quite recently become the focus of much attention in numerous pathological contexts, including neurodegenerative diseases, kidney and cardiovascular disease. Imbalance in ROS formation and degradation has also been implicated in essential hypertension. Essential hypertension is characterized by multiple genetic and environmental factors which do not completely explain its associated risk factors. Thereby, even if advances in therapy have led to a significant reduction in hypertension-associated complications, to interfere with the unbalance of redox signals might represent an additional therapeutic challenge. The decrease of nitric oxide (NO) levels, the antioxidant activity commonly found in preclinical models of hypertension and the ability of antioxidant approaches to reduce ROS levels have spurred clinicians to investigate the contribution of ROS in humans. Indeed, particular effort has recently been devoted to understanding how redox signaling may contribute to vascular pathobiology in human hypertension. However, although biomarkers of oxidative stress have been found to positively correlate with blood pressure in preclinical model of hypertension, human data are less convincing. We herein provide an overview of the most relevant mechanisms via which oxidative stress might contribute to the pathophysiology of essential hypertension. Moreover, alternative approaches, which are directed towards improving antioxidant machinery and/or interfering with ROS production, are also discussed. Full article

(This article belongs to the Special Issue Oxidative Stress in Vascular Diseases)

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