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Molecular Mechanisms of Cardioprotection

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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 (30 April 2022) | Viewed by 24836

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Dr. Táňa Ravingerová

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Guest Editor

Department of Cardiovascular Physiology and Pathophysiology, Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
Interests: ischemic injury of the heart, anti-ischemic protection; lifestyle-related diseases, cardiac adaptation, conditioning, molecular mechanisms of innate cardioprotection

Prof. Dr. Adriana Duris Adameova

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Co-Guest Editor

(1) Faculty of Pharmacy, Comenius University in Bratislava, Slovakia
(2) Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
Interests: myocardial ischemia/reperfusion injury, heart failure, cell death, cardiovascular pharmacology

Special Issue Information

Dear Colleagues,

Despite the progress in pharmacotherapy, interventional cardiology and surgery—cardiovascular diseases, especially ischemic heart disease (IHD), as a leading cause of heart failure (HF) and death worldwide—are expected to rise over the coming decades. This is due to the aging population and longer survival of patients after acute myocardial infarction (MI) with gradual development of HF and comorbidities, such as diabetes, hypertension, and dyslipidemia. Experimental studies revealed the protective effects of various forms of myocardial “preconditioning“ that were not always successful in clinical settings, and their novel clinically acceptable and safer forms. Currently, cellular mechanisms activated by novel forms of cardioprotection are not yet completely elucidated. In line with international translation-oriented research, this Special Issue will be dedicated to the recent research progress, providing an in-depth understanding of the triggering mechanisms of protection, cell signaling pathways, and target structures involved in reduction of heart injury (mitochondrial permeability transition pore (MPTP), and nuclear PPAR receptors). Special emphasis will be placed on the impact of comorbidities, age and gender on the adaptive processes considering functional, structural and subcellular cardiac alterations, as well as on the benefits of combination therapy. The goal of this Special issue is to provide an in-depth understanding of the molecular mechanisms of innate cardioprotection that may lead to development of novel/modified strategies of IHD management and prevention of HF.

Dr. Táňa Ravingerová
Prof. Dr. Adriana Duris Adameova
Guest Editor

Manuscript Submission Information

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Keywords

Myocardial infarction
Heart failure
Innate cardioprotection
Preconditioning
Remote conditioning
Postconditioning
Intermittent hypoxia
Physical activity
Cell signaling cascades
Mitochondrial function and metabolism
Aging
Hypertension
Diabetes
Combination therapy

Published Papers (9 papers)

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Research

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15 pages, 1840 KiB

Open AccessArticle

Network-Assisted Systems Biology Analysis of the Mitochondrial Proteome in a Pre-Clinical Model of Ischemia, Revascularization and Post-Conditioning

by Alex Gallinat, Gemma Vilahur, Teresa Padró and Lina Badimon

Int. J. Mol. Sci. 2022, 23(4), 2087; https://doi.org/10.3390/ijms23042087 - 14 Feb 2022

Cited by 7 | Viewed by 2314

Abstract

Infarct size is the major risk predictor for developing heart failure after an acute myocardial infarction (AMI). The discovery of the conditioning phenomena (i.e., repetitive brief cycles of ischemia applied either before or after a prolonged ischemic insult) has highlighted the existence of endogenous protective mechanisms of the heart potentially limiting infarct size after revascularization. However, most cardioprotective strategies, aiming at infarct size reduction, have failed in clinical studies. Thus, cardioprotection is an unmet clinical need. In the present study, we took a network-assisted systems biology approach to explore the mitochondrial proteomic signature of the myocardium after ischemia, ischemia with direct revascularization, and ischemia with re-establishment of blood flow by post-conditioning in a swine model of AMI. Furthermore, network extension with the ENCODE project human regulatory data allowed the prediction of potential transcription factors at play in the response to post-conditioning of the myocardium. Collectively, our results identify cardiac metabolism as a driver of cardioprotection, highlighting a dual role for post-conditioning promoting metabolic reprogramming of the myocardium, and a protective response mediated by VDAC2 and DJ-1 in the mitochondria. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardioprotection)

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16 pages, 3302 KiB

Open AccessArticle

Metabolites and Genes behind Cardiac Metabolic Remodeling in Mice with Type 1 Diabetes Mellitus

by Tyler N. Kambis, Hamid R. Shahshahan and Paras K. Mishra

Int. J. Mol. Sci. 2022, 23(3), 1392; https://doi.org/10.3390/ijms23031392 - 26 Jan 2022

Cited by 1 | Viewed by 3119

Abstract

Metabolic remodeling is at the heart of diabetic cardiomyopathy. High glycemic fluctuations increase metabolic stress in the type 1 diabetes mellitus (T1DM) heart. There is a lack of understanding on how metabolites and genes affect metabolic remodeling in the T1DM heart. We hypothesize that differential expression of metabolic genes and metabolites synergistically influence metabolic remodeling preceding T1DM cardiomyopathy. To test our hypothesis, we conducted high throughput analysis of hearts from adult male hyperglycemic Ins2^+/− (Akita) and littermate normoglycemic Ins2^+/+ (WT) mice. The Akita mouse is a spontaneous, genetic model of T1DM that develops increased levels of consistent glycemic variability without the off-target cardiotoxic effects present in chemically- induced models of T1DM. After validating the presence of a T1DM phenotype, we conducted metabolomics via LC-MS analysis and genomics via next-generation sequencing in left ventricle tissue from the Akita heart. Ingenuity Pathway Analyses revealed that 108 and 30 metabolic pathways were disrupted within the metabolomics and genomics datasets, respectively. Notably, a comparison between the two analyses showed 15 commonly disrupted pathways, including ketogenesis, ketolysis, cholesterol biosynthesis, acetyl CoA hydrolysis, and fatty acid biosynthesis and beta-oxidation. These identified metabolic pathways predicted by the differential expression of metabolites and genes provide the foundation for understanding metabolic remodeling in the T1DM heart. By limited experiment, we revealed a predicted disruption in the metabolites and genes behind T1DM cardiac metabolic derangement. Future studies targeting these genes and metabolites will unravel novel therapies to prevent/improve metabolic remodeling in the T1DM heart. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardioprotection)

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10 pages, 1031 KiB

Open AccessArticle

Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases

by Carolin Torregroza, Chiara O. Glashoerster, Katharina Feige, Martin Stroethoff, Annika Raupach, André Heinen, Markus W. Hollmann and Ragnar Huhn

Int. J. Mol. Sci. 2021, 22(22), 12471; https://doi.org/10.3390/ijms222212471 - 19 Nov 2021

Cited by 3 | Viewed by 1964

Abstract

The osmodiuretic agent Mannitol exerts cardioprotection against ischemia and reperfusion (I/R) injury when applied as a pre- and/or postconditioning stimulus. Previously, we demonstrated that these properties are mediated via the activation of mitochondrial ATP-sensitive potassium (mK_ATP) channels. However, considering Mannitol remains in the extracellular compartment, the question arises as to which receptor and intracellular signaling cascades are involved in myocardial protection by the osmodiuretic substance. Protein kinase B (Akt) and G (PKG), as part of the reperfusion injury salvage kinase (RISK) and/or endothelial nitric oxide (eNOS)/PKG pathway, are two well-investigated intracellular targets conferring myocardial protection upstream of mitochondrial potassium channels. Adenosine receptor subtypes have been shown to trigger different cardioprotective pathways, for example, the reperfusion injury. Further, Mannitol induces an increased activation of the adenosine 1 receptor (A1R) in renal cells conferring its nephroprotective properties. Therefore, we investigated whether (1) Akt and PKG are possible signaling targets involved in Mannitol-induced conditioning upstream of the mK_ATP channel and/or whether (2) cardioprotection by Mannitol is mediated via activation of the A1R. All experiments were performed on male Wistar rats in vitro employing the Langendorff isolated heart perfusion technique with infarct size determination as the primary endpoint. To unravel possible protein kinase activation, Mannitol was applied in combination with the Akt (MK2206) or PKG (KT5823) inhibitor. In further groups, an A1R blocker (DPCPX) was given with or without Mannitol. Preconditioning with Mannitol (Man) significantly reduced the infarct size compared to the control group. Co-administration of the A1R blocker DPXPC fully abolished myocardial protection of Mannitol. Interestingly and in contrast to the initial hypothesis, neither administration of the Akt nor the PKG blocker had any impact on the cardioprotective properties of Mannitol-induced preconditioning. These results are quite unexpected and show that the protein kinases Akt and PKG—as possible targets of known protective signaling cascades—are not involved in Mannitol-induced preconditioning. However, the cardioprotective effects of Mannitol are mediated via the A1R. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardioprotection)

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17 pages, 3465 KiB

Open AccessArticle

Alterations in ACE and ACE2 Activities and Cardiomyocyte Signaling Underlie Improved Myocardial Function in a Rat Model of Repeated Remote Ischemic Conditioning

by Beáta Bódi, Patrick M. Pilz, Lilla Mártha, Miriam Lang, Ouafa Hamza, Miklós Fagyas, Petra L. Szabó, Dietmar Abraham, Attila Tóth, Bruno K. Podesser, Attila Kiss and Zoltán Papp

Int. J. Mol. Sci. 2021, 22(20), 11064; https://doi.org/10.3390/ijms222011064 - 14 Oct 2021

Cited by 1 | Viewed by 1710

Abstract

Post-ischemic left ventricular (LV) remodeling and its hypothetical prevention by repeated remote ischemic conditioning (rRIC) in male Sprague–Dawley rats were studied. Myocardial infarction (MI) was evoked by permanent ligation of the left anterior descending coronary artery (LAD), and myocardial characteristics were tested in the infarcted anterior and non-infarcted inferior LV regions four and/or six weeks later. rRIC was induced by three cycles of five-minute-long unilateral hind limb ischemia and five minutes of reperfusion on a daily basis for a period of two weeks starting four weeks after LAD occlusion. Sham operated animals served as controls. Echocardiographic examinations and invasive hemodynamic measurements revealed distinct changes in LV systolic function between four and six weeks after MI induction in the absence of rRIC (i.e., LV ejection fraction (LVEF) decreased from 52.8 ± 2.1% to 50 ± 1.6%, mean ± SEM, p < 0.05) and in the presence of rRIC (i.e., LVEF increased from 48.2 ± 4.8% to 55.2 ± 4.1%, p < 0.05). Angiotensin-converting enzyme (ACE) activity was about five times higher in the anterior LV wall at six weeks than that in sham animals. Angiotensin-converting enzyme 2 (ACE2) activity roughly doubled in post-ischemic LVs. These increases in ACE and ACE2 activities were effectively mitigated by rRIC. Ca²⁺-sensitivities of force production (pCa₅₀) of LV permeabilized cardiomyocytes were increased at six weeks after MI induction together with hypophosphorylation of 1) cardiac troponin I (cTnI) in both LV regions, and 2) cardiac myosin-binding protein C (cMyBP-C) in the anterior wall. rRIC normalized pCa₅₀, cTnI and cMyBP-C phosphorylations. Taken together, post-ischemic LV remodeling involves region-specific alterations in ACE and ACE2 activities together with changes in cardiomyocyte myofilament protein phosphorylation and function. rRIC has the potential to prevent these alterations and to improve LV performance following MI. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardioprotection)

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18 pages, 2440 KiB

Open AccessArticle

Impact of Maturation on Myocardial Response to Ischemia and the Effectiveness of Remote Preconditioning in Male Rats

by Lucia Kindernay, Veronika Farkasova, Jan Neckar, Jaroslav Hrdlicka, Kirsti Ytrehus and Tanya Ravingerova

Int. J. Mol. Sci. 2021, 22(20), 11009; https://doi.org/10.3390/ijms222011009 - 12 Oct 2021

Cited by 8 | Viewed by 1752

Abstract

Aging attenuates cardiac tolerance to ischemia/reperfusion (I/R) associated with defects in protective cell signaling, however, the onset of this phenotype has not been completely investigated. This study aimed to compare changes in response to I/R and the effects of remote ischemic preconditioning (RIPC) in the hearts of younger adult (3 months) and mature adult (6 months) male Wistar rats, with changes in selected proteins of protective signaling. Langendorff-perfused hearts were exposed to 30 min I/120 min R without or with prior three cycles of RIPC (pressure cuff inflation/deflation on the hind limb). Infarct size (IS), incidence of ventricular arrhythmias and recovery of contractile function (LVDP) served as the end points. In both age groups, left ventricular tissue samples were collected prior to ischemia (baseline) and after I/R, in non-RIPC controls and in RIPC groups to detect selected pro-survival proteins (Western blot). Maturation did not affect post-ischemic recovery of heart function (Left Ventricular Developed Pressure, LVDP), however, it increased IS and arrhythmogenesis accompanied by decreased levels and activity of several pro-survival proteins and by higher levels of pro-apoptotic proteins in the hearts of elder animals. RIPC reduced the occurrence of reperfusion-induced ventricular arrhythmias, IS and contractile dysfunction in younger animals, and this was preserved in the mature adults. RIPC did not increase phosphorylated protein kinase B (p-Akt)/total Akt ratio, endothelial nitric oxide synthase (eNOS) and protein kinase Cε (PKCε) prior to ischemia but only after I/R, while phosphorylated glycogen synthase kinase-3β (GSK3β) was increased (inactivated) before and after ischemia in both age groups coupled with decreased levels of pro-apoptotic markers. We assume that resistance of rat heart to I/R injury starts to already decline during maturation, and that RIPC may represent a clinically relevant cardioprotective intervention in the elder population. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardioprotection)

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18 pages, 2087 KiB

Open AccessArticle

Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling

by Csaba Horvath, Megan Young, Izabela Jarabicova, Lucia Kindernay, Kristina Ferenczyova, Tanya Ravingerova, Martin Lewis, M. Saadeh Suleiman and Adriana Adameova

Int. J. Mol. Sci. 2021, 22(15), 7983; https://doi.org/10.3390/ijms22157983 - 26 Jul 2021

Cited by 21 | Viewed by 3476

Abstract

Receptor-interacting protein kinase 3 (RIP3) is a convergence point of multiple signalling pathways, including necroptosis, inflammation and oxidative stress; however, it is completely unknown whether it underlies acute myocardial ischemia/reperfusion (I/R) injury. Langendorff-perfused rat hearts subjected to 30 min ischemia followed by 10 min reperfusion exhibited compromised cardiac function which was not abrogated by pharmacological intervention of RIP3 inhibition. An immunoblotting analysis revealed that the detrimental effects of I/R were unlikely mediated by necroptotic cell death, since neither the canonical RIP3–MLKL pathway (mixed lineage kinase-like pseudokinase) nor the proposed non-canonical molecular axes involving CaMKIIδ–mPTP (calcium/calmodulin-dependent protein kinase IIδ–mitochondrial permeability transition pore), PGAM5–Drp1 (phosphoglycerate mutase 5–dynamin-related protein 1) and JNK–BNIP3 (c-Jun N-terminal kinase–BCL2-interacting protein 3) were activated. Similarly, we found no evidence of the involvement of NLRP3 inflammasome signalling (NOD-, LRR- and pyrin domain-containing protein 3) in such injury. RIP3 inhibition prevented the plasma membrane rupture and delayed mPTP opening which was associated with the modulation of xanthin oxidase (XO) and manganese superoxide dismutase (MnSOD). Taken together, this is the first study indicating that RIP3 regulates early reperfusion injury via oxidative stress- and mitochondrial activity-related effects, rather than cell loss due to necroptosis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardioprotection)

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Review

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17 pages, 1277 KiB

Open AccessReview

Dynamic Involvement of Telocytes in Modulating Multiple Signaling Pathways in Cardiac Cytoarchitecture

by Ioana Cucu, Mihnea Ioan Nicolescu, Ștefan-Sebastian Busnatu and Cătălin Gabriel Manole

Int. J. Mol. Sci. 2022, 23(10), 5769; https://doi.org/10.3390/ijms23105769 - 21 May 2022

Cited by 8 | Viewed by 3002

Abstract

Cardiac interstitium is a complex and dynamic environment, vital for normal cardiac structure and function. Telocytes are active cellular players in regulating main events that feature myocardial homeostasis and orchestrating its involvement in heart pathology. Despite the great amount of data suggesting (microscopically, proteomically, genetically, etc.) the implications of telocytes in the different physiological and reparatory/regenerative processes of the heart, understanding their involvement in realizing the heart’s mature cytoarchitecture is still at its dawn. Our scrutiny of the recent literature gave clearer insights into the implications of telocytes in the WNT signaling pathway, but also TGFB and PI3K/AKT pathways that, inter alia, conduct cardiomyocytes differentiation, maturation and final integration into heart adult architecture. These data also strengthen evidence for telocytes as promising candidates for cellular therapies in various heart pathologies. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardioprotection)

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19 pages, 1433 KiB

Open AccessReview

Modification of Ischemia/Reperfusion-Induced Alterations in Subcellular Organelles by Ischemic Preconditioning

by Paramjit S. Tappia, Anureet K. Shah, Bram Ramjiawan and Naranjan S. Dhalla

Int. J. Mol. Sci. 2022, 23(7), 3425; https://doi.org/10.3390/ijms23073425 - 22 Mar 2022

Cited by 12 | Viewed by 2770

Abstract

It is now well established that ischemia/reperfusion (I/R) injury is associated with the compromised recovery of cardiac contractile function. Such an adverse effect of I/R injury in the heart is attributed to the development of oxidative stress and intracellular Ca²⁺-overload, which are known to induce remodeling of subcellular organelles such as sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils. However, repeated episodes of brief periods of ischemia followed by reperfusion or ischemic preconditioning (IP) have been shown to improve cardiac function and exert cardioprotective actions against the adverse effects of prolonged I/R injury. This protective action of IP in attenuating myocardial damage and subcellular remodeling is likely to be due to marked reductions in the occurrence of oxidative stress and intracellular Ca²⁺-overload in cardiomyocytes. In addition, the beneficial actions of IP have been attributed to the depression of proteolytic activities and inflammatory levels of cytokines as well as the activation of the nuclear factor erythroid factor 2-mediated signal transduction pathway. Accordingly, this review is intended to describe some of the changes in subcellular organelles, which are induced in cardiomyocytes by I/R for the occurrence of oxidative stress and intracellular Ca²⁺-overload and highlight some of the mechanisms for explaining the cardioprotective effects of IP. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardioprotection)

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14 pages, 1291 KiB

Open AccessReview

A Brief Review on the Biology and Effects of Cellular and Circulating microRNAs on Cardiac Remodeling after Infarction

by Mihir Parikh and Grant N. Pierce

Int. J. Mol. Sci. 2021, 22(9), 4995; https://doi.org/10.3390/ijms22094995 - 8 May 2021

Cited by 9 | Viewed by 3163

Abstract

Despite advances in diagnostic, prognostic, and treatment modalities, myocardial infarction (MI) remains a leading cause of morbidity and mortality. Impaired cellular signaling after an MI causes maladaptive changes resulting in cardiac remodeling. MicroRNAs (miRNAs/miR) along with other molecular components have been investigated for their involvement in cellular signaling in the pathogenesis of various cardiac conditions like MI. miRNAs are small non-coding RNAs that negatively regulate gene expression. They bind to complementary mRNAs and regulate the rate of protein synthesis by altering the stability of their targeted mRNAs. A single miRNA can modulate several cellular signaling pathways by targeting hundreds of mRNAs. This review focuses on the biogenesis and beneficial effects of cellular and circulating (exosomal) miRNAs on cardiac remodeling after an MI. Particularly, miR-1, -133, 135, and -29 that play an essential role in cardiac remodeling after an MI are described in detail. The limitations that will need to be addressed in the future for the further development of miRNA-based therapeutics for cardiovascular conditions will also be discussed. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardioprotection)

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