Research Progress on the Mechanism of Lysosome in Myocardial Ischemia-Reperfusion Injury Based on Autophagy.

In recent years, the interaction of intracellular organelles such as mitochondria and lysosomal functions has attracted increasing attention. Recent evidence suggests that mitochondrion-lysosomal contact plays a key role in regulating lysosomal biogenesis and maintaining cellular homeostasis. Myocardial ischemia and reperfusion will lead to corresponding changes in the autophagy flux in cardiomyocytes, and lysosomes are a key link in the process of autophagy, and the fusion of lysosomes and autophagosomes is an essential link in the occurrence of autophagy. Therefore, the function and homeostasis of lysosomes also undergo different changes during myocardial ischemia and reperfusion. Lysosomal-related biological factors and membrane proteins also play different roles. This article will review the mechanism of lysosomes in myocardial ischemia-reperfusion injury and the research progress of lysosomal-related proteins.

Autosis: a new form of cell death in myocardial ischemia-reperfusion injury.

Cardiomyocytes undergo a variety of cell death events during myocardial ischemia‒reperfusion injury (MIRI). Understanding the causes of cardiomyocyte mortality is critical for the prevention and treatment of MIRI. Among the various types of cell death, autosis is a recently identified type of autophagic cell death with distinct morphological and chemical characteristics. Autosis can be attenuated by autophagy inhibitors but not reversed by apoptosis or necrosis inhibitors. In recent years, it has been shown that during the late phase of reperfusion, autosis is activated, which exacerbates myocardial injury. This article describes the characteristics of autosis, autophagic cell death, and the relationship between autophagic cell death and autosis; reviews the mechanism of autosis in MIRI; and discusses its clinical significance.

cFLIPL alleviates myocardial ischemia-reperfusion injury by regulating pyroptosis.

Alleviating myocardial ischemia-reperfusion injury (MIRI) plays a critical role in the prognosis and improvement of cardiac function following acute myocardial infarction. Pyroptosis is a newly identified form of cell death that has been implicated in the regulation of MIRI. In our study, H9c2 cells and SD rats were transfected using a recombinant adenovirus vector carrying cFLIPL , and the transfection was conducted for 3 days. Subsequently, H9c2 cells were subjected to 4 h of hypoxia followed by 12 h of reoxygenation to simulate an in vitro ischemia-reperfusion model. SD rats underwent 30 min of ischemia followed by 2 h of reperfusion to establish an MIRI model. Our findings revealed a notable decrease in cFLIPL expression in response to ischemia/reperfusion (I/R) and hypoxia/reoxygenation (H/R) injuries. Overexpression of cFLIPL can inhibit pyroptosis, reducing myocardial infarction area in vivo, and enhancing H9c2 cell viability in vitro. I/R and H/R injuries induced the upregulation of ASC, cleaved Caspase 1, NLRP3, GSDMD-N, IL-1ß, and IL-18 proteins, promoting cell apoptosis. Our research indicates that cFLIPL may suppress pyroptosis by strategically binding with Caspase 1, inhibiting the release of inflammatory cytokines and preventing cell membrane rupture. Therefore, cFLIPL could potentially serve as a promising target for alleviating MIRI by suppressing the pyroptotic pathway.

Role of M6a Methylation in Myocardial Ischemia-Reperfusion Injury and Doxorubicin-Induced Cardiotoxicity.

Cardiovascular disease remains the leading cause of death worldwide, with acute myocardial infarction and anticancer drug-induced cardiotoxicity being the significant factors. The most effective treatment for acute myocardial infarction is rapid restoration of coronary blood flow by thrombolytic therapy or percutaneous coronary intervention. However, myocardial ischemia-reperfusion injury (MI/RI) after reperfusion therapy is common in acute myocardial infarction, thus affecting the prognosis of patients with acute myocardial infarction. There is no effective treatment for MI/RI. Anthracyclines such as Doxorubicin (DOX) have limited clinical use due to their cardiotoxicity, and the mechanism of DOX-induced cardiac injury is complex and not yet fully understood. N6-methyladenosine (m6A) plays a crucial role in many biological processes. Emerging evidence suggests that m6A methylation plays a critical regulatory role in MI/RI and DOX-induced cardiotoxicity (DIC), suggesting that m6A may serve as a novel biomarker and therapeutic target for MI/RI and DIC. M6A methylation may mediate the pathophysiological processes of MI/RI and DIC by regulating cellular autophagy, apoptosis, oxidative stress, and inflammatory response. In this paper, we first focus on the relationship between m6A methylation and MI/RI, then further elucidate that m6A methylation may mediate the pathophysiological process of MI/RI through the regulation of cellular autophagy, apoptosis, oxidative stress, and inflammatory response. Finally, briefly outline the roles played by m6A in DIC, which will provide a new methodology and direction for the research and treatment of MI/RI and DIC.

Research Progress on Histone Deacetylases Regulating Programmed Cell Death in Atherosclerosis.

Histone deacetylases (HDACs) are epigenetic modifying enzyme that is closely related to chromatin structure and gene transcription, and numerous studies have found that HDACs play an important regulatory role in atherosclerosis disease. Apoptosis, autophagy and programmed necrosis as the three typical programmed cell death modalities that can lead to cell loss and are closely related to the developmental process of atherosclerosis. In recent years, accumulating evidence has shown that the programmed cell death mediated by HDACs is increasingly important in the pathophysiology of atherosclerosis. This paper first gives a brief overview of HDACs, the mechanism of programmed cell death, and their role in atherosclerosis, and then further elaborates on the role and mechanism of HDACs in regulating apoptosis, autophagy, and programmed necrosis in atherosclerosis, respectively, to provide new effective measures and theoretical basis for the prevention and treatment of atherosclerosis.

Liraglutide Attenuates Myocardial Ischemia/Reperfusion Injury Through the Inhibition of Necroptosis by Activating GLP-1R/PI3K/Akt Pathway.

Necroptosis is a crucial programmed cell death that is tightly associated with myocardial ischemia/reperfusion injury (MI/RI). Liraglutide is an effective option for the treatment of type 2 diabetes and has recently been reported to exert cardioprotective effects on MI/RI. Researchers do not know whether the cardioprotective effect of liraglutide is involved in regulating necroptosis. This study aimed to explore the effect of liraglutide on MI/RI-induced necroptosis and its potential mechanisms. Hypoxia/reoxygenation (H/R) was performed on H9c2 cells in vitro to simulate ischemia/reperfusion (I/R) injury, and an MI/RI rat model was established in vivo by ligating the anterior descending branch of the left coronary artery. H/R or I/R damage was assessed by performing biochemical assay, Hoechst 33342/PI staining, H&E (hematoxylin and eosin) staining, and Annexin-V/PI staining. Our data revealed that liraglutide resulted in markedly increased cell viability and reduced cardiac enzyme release by protecting cardiomyocytes from a necrosis-like phenotype after H/R. The myocardial infarct size and cardiac enzyme release were reduced in the heart tissues from the liraglutide-treated group. The levels of necroptosis-associated proteins (receptor-interacting protein kinase 3 (RIPK3), p-RIPK3, and phosphorylated-mixed lineage kinase domain-like protein (p-MLKL)) were also reduced by the liraglutide treatment. Mechanistically, we revealed that liraglutide exerted cardioprotective effects through a glucagon-like peptide-1 receptor (GLP-1R) and phosphatidylinositol-3 kinase (PI3K)-dependent pathway. Both the GLP-1R inhibitor exendin (9-39) and the PI3K inhibitor LY294002 abrogated the protective effects of liraglutide in vitro. We found that liraglutide may attenuate MI/RI by inhibiting necroptosis, in part by enhancing the activity of the GLP-1R/PI3K/Akt pathway.

Clinical efficacy of sacubitril-valsartan combined with acute ST-segment elevation myocardial infarction after reperfusion: A systematic review and meta-analysis.

Background: Several studies have investigated the combined use of sacubitril- valsartan after reperfusion in acute ST-segment elevation myocardial infarction (STEMI). However, the sample sizes of these studies were small and their results were somewhat heterogeneous. To determine the effect of sacubitril-valsartan on myocardial ischemia-reperfusion. Methods: Search PubMed, EMbase, Web of Science and The Cochrane Library, CNKI database, VIP database and Wanfang digital journal full-text database for eligible articles from their date of inception up to April, 2022. All data were meta-analyzed using Review Manager 5.3 and STATA 16.0 software. Results: A total of 23 studies including 2,326 patients with acute STEMI were included. These results of this meta-analysis indicated that left ventricular ejection fractions (LVEF) value within 6 months after surgery (OR, 4.29; 95% confidence interval, 3.78-4.80; P < 0.00001), left ventricular end-diastolic diameter (LVEDD) value within 6 months after surgery (OR, -3.11; 95% CI, -3.87 to -2.35; P < 0.00001) and left ventricular end-diastolic volume (LVEDV) value 6 months after operation (OR, -6.22; 95% CI, -7.10 to -5.35; P < 0.00001) are better than without sacubitril and valsartan. Conclusion: To sum up the above, the results of this study suggest that sacubitril- valsartan can reduce the reperfusion injury of ischemic myocardium by improving cardiac function within a follow-up period of 6 months.