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Cells Sep 2020During the last three decades, timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous intervention (pPCI) has allowed amazing... (Review)
Review
During the last three decades, timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous intervention (pPCI) has allowed amazing improvements in outcomes with a more than halving in 1-year ST-elevation myocardial infarction (STEMI) mortality. However, mortality and left ventricle (LV) remodeling remain substantial in these patients. As such, novel therapeutic interventions are required to reduce myocardial infarction size, preserve LV systolic function, and improve survival in reperfused-STEMI patients. Myocardial ischemia-reperfusion injury (MIRI) prevention represents the main goal to reach in order to reduce STEMI mortality. There is currently no effective therapy for MIRI prevention in STEMI patients. A significant reason for the weak and inconsistent results obtained in this field may be the presence of multiple, partially redundant, mechanisms of cell death during ischemia-reperfusion, whose relative importance may depend on the conditions. Therefore, it is always more recognized that it is important to consider a "multi-targeted cardioprotective therapy", defined as an additive or synergistic cardioprotective agents or interventions directed to distinct targets with different timing of application (before, during, or after pPCI). Given that some neprilysin (NEP) substrates (natriuretic peptides, angiotensin II, bradykinin, apelins, substance P, and adrenomedullin) exert a cardioprotective effect against ischemia-reperfusion injury, it is conceivable that antagonism of proteolytic activity by this enzyme may be considered in a multi-targeted strategy for MIRI prevention. In this review, by starting from main pathophysiological mechanisms promoting MIRI, we discuss cardioprotective effects of NEP substrates and the potential benefit of NEP pharmacological inhibition in MIRI prevention.
Topics: Adrenomedullin; Aminobutyrates; Angiotensin II; Animals; Apelin; Atrial Natriuretic Factor; Biphenyl Compounds; Bradykinin; Cardiotonic Agents; Drug Combinations; Gene Expression Regulation; Humans; Mice; Myocardial Reperfusion Injury; Neprilysin; ST Elevation Myocardial Infarction; Substance P; Survival Analysis; Tetrazoles; Valsartan; Ventricular Remodeling
PubMed: 32967374
DOI: 10.3390/cells9092134 -
Cardiovascular Drugs and Therapy Feb 2020Despite an increase in the rates of survival in patients suffering myocardial infarction, as yet there is no therapy specifically targeting ischaemia and reperfusion... (Review)
Review
Despite an increase in the rates of survival in patients suffering myocardial infarction, as yet there is no therapy specifically targeting ischaemia and reperfusion injury of the myocardium. With a greater understanding of immune activation during infarction, more potential treatment targets are now being identified. The innate immune system is believed to play an important role in the myocardium after ischaemia-driven cardiomyocyte death. The release of intracellular contents including DNA into the extracellular space during necrosis and cell rupture is now believed to create a pro-inflammatory milieu which propagates the inflammatory process. DNA and DNA fragments have been shown to activate the innate immune system by acting as Danger-Associated Molecular Patterns (DAMPs), which act as ligands on toll-like receptors (TLRs). Stimulation of TLRs, in turn, can activate intracellular cell death pathways such as pyroptosis. Here, we review the role of DNA fragments during ischaemia and reperfusion, and assess their potential as a target in the quest to preserve cardiomyocyte viability following myocardial infarction.
Topics: Alarmins; Cell-Free Nucleic Acids; DNA; Histones; Humans; Immunity, Innate; Inflammasomes; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Pyroptosis; Signal Transduction
PubMed: 32062794
DOI: 10.1007/s10557-020-06946-6 -
PloS One 2023The purpose of this research was to verify that vericiguat, a soluble guanylate cyclase (sGC) stimulator, reduces myocardial ischemic reperfusion injury (MIRI), and to...
BACKGROUND
The purpose of this research was to verify that vericiguat, a soluble guanylate cyclase (sGC) stimulator, reduces myocardial ischemic reperfusion injury (MIRI), and to learn how this reduction happens.
METHODS AND RESULTS
To develop an ischaemia/reperfusion (I/R) model, the left anterior descending artery was blocked in minipigs under anesthesia for 90 minutes, followed by 180 minutes of reperfusion. Vericiguat is administered three hours before surgery. Two weeks after receiving therapy, pigs underwent cardiovascular magnetic resonance imaging (MRI) to evaluate the results. The MRI results suggest improvement in the myocardial infarct after vericiguat treatment. Vericiguat treatment for two weeks enhanced vascularity, inhibited pro-inflammatory cells, and decreased collagen deposition in the infarct zone of pigs. Short-term experiments investigating possible explanations have indicated that vericiguat has antiapoptotic effects on cardiomyocytes and increases levels of autophagy.
CONCLUSIONS
Vericiguat, an SGC activator, reduces MIRI in pigs by boosting autophagy, preventing apoptosis, and promoting angiogenesis.
Topics: Swine; Animals; Swine, Miniature; Myocardial Infarction; Myocytes, Cardiac; Myocardial Reperfusion Injury; Reperfusion
PubMed: 38134018
DOI: 10.1371/journal.pone.0295566 -
Medical Science Monitor : International... Jan 2021BACKGROUND We aimed to explore the effect of parecoxib sodium on myocardial ischemia-reperfusion (I/R) injury rats and its mechanism. MATERIAL AND METHODS The coronary...
BACKGROUND We aimed to explore the effect of parecoxib sodium on myocardial ischemia-reperfusion (I/R) injury rats and its mechanism. MATERIAL AND METHODS The coronary artery of Sprague-Dawley rats was occluded for 6 h of myocardial ischemia, followed by reperfusion for 30 min (I/R group). Before ischemia, parecoxib sodium (10 mg/kg) was intraperitoneally injected twice a day for 3 consecutive days, followed by reperfusion for 6 h (I/R+Pare group). The cardiac function and changes in the infarction area were evaluated via echocardiography in each group. The differences in the expressions of apoptosis-related proteins were determined via immunohistochemistry and western blotting. Then, the percentage of reactive oxygen species (ROS)⁺ cells and the content of lipid peroxide were detected, based on which the degree of oxidative stress was evaluated. Next, the expressions of nuclear factor-kappaB (NF-kappaB) and nuclear factor E2-related factor 2 (Nrf-2) signaling pathways and downstream target genes were determined using real-time quantitative polymerase chain reaction (PCR). RESULTS After treatment with parecoxib sodium, the cardiac function of I/R injury rats was restored, and the infarction area and apoptosis level were reduced (P<0.05). Parecoxib sodium reduced the levels of ROS and lipid peroxidation in myocardial I/R injury rats, thereby weakening oxidative stress. It also regulated the redox imbalance caused by I/R injury through regulating NF-kappaB and Nrf-2 (P<0.01). In addition, after treatment with parecoxib sodium, NF-kappaB was significantly downregulated, while Nrf-2 was upregulated, and the content of proinflammatory cytokines was obviously reduced (P<0.01). CONCLUSIONS Parecoxib sodium exerts a protective effect against myocardial I/R injury through regulating antioxidant and inflammatory mechanisms.
Topics: Animals; Apoptosis; Cardiotonic Agents; Cytokines; Heart Function Tests; Inflammation Mediators; Isoxazoles; Myocardial Reperfusion Injury; Myocardium; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Rats, Sprague-Dawley; Signal Transduction; Rats
PubMed: 33395402
DOI: 10.12659/MSM.928205 -
Aging Cell Sep 2023Age-related sensors Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) play an essential role in the protective response upon myocardial ischemia and/or reperfusion (I/R). However,...
Age-related sensors Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) play an essential role in the protective response upon myocardial ischemia and/or reperfusion (I/R). However, the subcellular localization and co-regulatory network between cardiac SIRT1 and SIRT3 remain unknown, especially their effects on age-related metabolic regulation during acute ischemia and I/R. Here, we found that defects of cardiac SIRT1 or SIRT3 with aging result in an exacerbated cardiac physiological structural and functional deterioration after acute ischemic stress and failed recovery through reperfusion operation. In aged hearts, SIRT1 translocated into mitochondria and recruited more mitochondria SIRT3 to enhance their interaction during acute ischemia, acting as adaptive protection for the aging hearts from further mitochondria dysfunction. Subsequently, SIRT3-targeted proteomics revealed that SIRT1 plays a crucial role in maintaining mitochondrial integrity through SIRT3-mediated substrate metabolism during acute ischemic and I/R stress. Although the loss of SIRT1/SIRT3 led to a compromised PGC-1α/PPARα-mediated transcriptional control of fatty acid oxidation in response to acute ischemia and I/R, their crosstalk in mitochondria plays a more important role in the aging heart during acute ischemia. However, the increased mitochondria SIRT1-SIRT3 interaction promoted adaptive protection to aging-related fatty acid metabolic disorder via deacetylation of long-chain acyl CoA dehydrogenase (LCAD) during ischemic insults. Therefore, the dynamic network of SIRT1/SIRT3 acts as a mediator that regulates adaptive metabolic response to improve the tolerance of aged hearts to ischemic insults, which will facilitate investigation into the role of SIRT1/SIRT3 in age-related ischemic heart disease.
Topics: Humans; Fatty Acids; Homeostasis; Sirtuin 1; Sirtuin 3; Myocardial Ischemia; Myocardial Reperfusion; Cardiovascular System
PubMed: 37537789
DOI: 10.1111/acel.13930 -
IUBMB Life Jan 2021Myocardial ischemia/reperfusion (I/R) injury greatly contributes to myocardial tissue damage in patients with coronary disease, which eventually leads to heart failure....
Myocardial ischemia/reperfusion (I/R) injury greatly contributes to myocardial tissue damage in patients with coronary disease, which eventually leads to heart failure. Long noncoding RNAs (lncRNAs) have an emerging role in the process of myocardial I/R injury. Our previous work revealed the protective role of miR-374a-5p against myocardial I/R injury. In this study, we explored the role of lncRNA TTTY15 and its potential interaction mechanisms with miR-374a-5p in myocardial I/R injury. The expression of TTTY15 was increased both in vitro and in vivo after myocardial I/R injury models according to quantitative real-time polymerase chain reaction. Various assays were conducted to evaluate the regulatory relationship among TTTY15, miR-374a-5p, FOXO1, and autophagy in H9c2 and HL-1 cells. The results showed that TTTY15 suppresses autophagy and myocardial I/R injury by targeting miR-374a-5p. We found that TTTY15 regulates miR-374a-5p, thus affecting FOXO1 expression and autophagy in myocytes during I/R. Furthermore, in an in vivo mouse model of myocardial I/R injury, suppression of TTTY15 successfully alleviated myocardial I/R injury. Our results reveal a novel feedback mechanism in which TTTY15 regulates miRNA processing and a potential target in myocardial I/R injury. TTTY15 is a promising therapeutic target for treating myocardial I/R injury.
Topics: Animals; Apoptosis; Autophagy; Cell Hypoxia; Forkhead Box Protein O1; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Myocardial Reperfusion Injury; RNA, Long Noncoding; Signal Transduction
PubMed: 33296140
DOI: 10.1002/iub.2428 -
Cells Sep 2021Myocardial ischemia-reperfusion (I/R) injury significantly alters heart function following infarct and increases the risk of heart failure. Many studies have sought to... (Review)
Review
Myocardial ischemia-reperfusion (I/R) injury significantly alters heart function following infarct and increases the risk of heart failure. Many studies have sought to preserve irreplaceable myocardium, termed cardioprotection, but few, if any, treatments have yielded a substantial reduction in clinical I/R injury. More research is needed to fully understand the molecular pathways that govern cardioprotection. Redox mechanisms, specifically cysteine oxidations, are acute and key regulators of molecular signaling cascades mediated by kinases. Here, we review the role of reactive oxygen species in modifying cysteine residues and how these modifications affect kinase function to impact cardioprotection. This exciting area of research may provide novel insight into mechanisms and likely lead to new treatments for I/R injury.
Topics: Animals; Cysteine; Humans; Myocardial Reperfusion Injury; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 34572037
DOI: 10.3390/cells10092388 -
Molecules (Basel, Switzerland) Jun 2021DJ-1 was originally identified as an oncogene product while mutations of the gene encoding DJ-1/PARK7 were later associated with a recessive form of Parkinson's disease.... (Review)
Review
DJ-1 was originally identified as an oncogene product while mutations of the gene encoding DJ-1/PARK7 were later associated with a recessive form of Parkinson's disease. Its ubiquitous expression and diversity of function suggest that DJ-1 is also involved in mechanisms outside the central nervous system. In the last decade, the contribution of DJ-1 to the protection from ischemia-reperfusion injury has been recognized and its involvement in the pathophysiology of cardiovascular disease is attracting increasing attention. This review describes the current and gaps in our knowledge of DJ-1, focusing on its role in regulating cardiovascular function. In parallel, we present original data showing an association between increased DJ-1 expression and antiapoptotic and anti-inflammatory markers following cardiac and vascular surgical procedures. Future studies should address DJ-1's role as a plausible novel therapeutic target for cardiovascular disease.
Topics: Animals; Biomarkers; Heart; Humans; Inflammation; Myocardial Reperfusion Injury; Myocardium; Protein Deglycase DJ-1
PubMed: 34206441
DOI: 10.3390/molecules26133795 -
Hamostaseologie Aug 2023Evidence has shown that microRNA (miR)-122-5p is a diagnostic biomarker of acute myocardial infarction. Here, we aimed to uncover the functions of miR-122-5p in the...
OBJECTIVE
Evidence has shown that microRNA (miR)-122-5p is a diagnostic biomarker of acute myocardial infarction. Here, we aimed to uncover the functions of miR-122-5p in the pathological process of myocardial ischemia-reperfusion injury (MI/RI).
METHODS
An MI/RI model was established by left anterior descending coronary artery ligation in mice. The levels of miR-122-5p, suppressor of cytokine signaling-1 (SOCS1), phosphorylation of Janus kinase 2 (p-JAK2), and signal transducers and activators of transcription (p-STAT3) in the myocardial tissues of mice were measured. Downregulated miR-122-5p or upregulated SOCS1 recombinant adenovirus vectors were injected into mice before MI/RI modeling. The cardiac function, inflammatory response, myocardial infarction area, pathological damage, and cardiomyocyte apoptosis in the myocardial tissues of mice were evaluated. Cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) injury and cardiomyocyte biological function was tested upon transfection of miR-122-5p inhibitor. The target relation between miR-122-5p and SOCS1 was evaluated.
RESULTS
miR-122-5p expression and p-JAK2 and p-STAT3 expression were high, and SOCS1 expression was low in the myocardial tissues of MI/RI mice. Decreasing miR-122-5p or increasing SOCS1 expression inactivated the JAK2/STAT3 pathway to alleviate MI/RI by improving cardiac function and reducing inflammatory reaction, myocardial infarction area, pathological damage, and cardiomyocyte apoptosis in mice. Silencing of SOCS1 reversed depleted miR-122-5p-induced cardioprotection for MI/RI mice. In vitro experiments revealed that the downregulation of miR-122-5p induced proliferative, migratory, and invasive capabilities of H/R cardiomyocytes while inhibiting apoptosis. Mechanically, SOCS1 was a target gene of miR-122-5p.
CONCLUSION
Our study summarizes that inhibition of miR-122-5p induces SOCS1 expression, thereby relieving MI/RI in mice.
Topics: Mice; Animals; Myocardial Reperfusion Injury; MicroRNAs; Myocytes, Cardiac; Myocardial Infarction; Myocardium
PubMed: 36882114
DOI: 10.1055/a-2013-0336 -
Biological & Pharmaceutical Bulletin Jul 2020Beta-asarone (β-Asarone), the major component of Acorus tatarinowii Rhizoma, has been proved to be muti-pharmacological activities including anti-inflammation, and...
Beta-asarone (β-Asarone), the major component of Acorus tatarinowii Rhizoma, has been proved to be muti-pharmacological activities including anti-inflammation, and which is effective in protecting the central nervous system. However, the effect of β-Asarone on myocardial ischemia-reperfusion (I/R) injury is not yet clear. This study used a rat model with 45 min occlusion and 24 h releasing of proximal segment of left anterior descending coronary artery. The effects of β-Asarone on cardiac histopathology, myocardial infarction size, levels of cardiac troponin T (cTNT), myeloperoxidase (MPO) and interleukin-1β (IL-1β), protein expressions of apoptosis-associated speck-like protein containing a CARD (ASC), Nod-like receptor protein 3 (NLRP3), caspase-1 and Gasdermin D (GSDMSD), and left ventricular performance were studied respectively. Our results showed that administration of β-Asarone significantly improved the heart outcome after myocardial ischemia and reperfusion in terms of less infarction size and lower serum cTNT concentration. Further, β-Asarone treatment evidently inhibited inflammatory response with less granulocyte infiltration, mild tissue edema and lower tissue MPO content, it also suppressed NLRP3 signal pathway and cardiac cell's pyroptosis for less protein expressions of ASC and NLRP3, lower level cleavage activation of caspase-1 and GSDMSD, and lower serum IL-1β concentration. Finally, β-Asarone treatment well preserved the left ventricular performance with higher ejection fraction and fractional shortening. The experimental results suggested that β-Asarone was protective against myocardial ischemia-reperfusion injury, in which inhibition of inflammatory response and suppression of NLRP3 inflammasome mediated pyroptosis were supposed to play a vital role.
Topics: Allylbenzene Derivatives; Animals; Anisoles; Fibrinolytic Agents; Inflammasomes; Inflammation Mediators; Male; Myocardial Reperfusion Injury; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Rats; Rats, Sprague-Dawley
PubMed: 32321872
DOI: 10.1248/bpb.b19-00926