Hydrogen sulfide (H2S) is now recognized as a third gaseous mediator along with nitric oxide (NO) and carbon monoxide (CO), though it was originally considered as a malodorous and toxic gas. H2S is produced endogenously from cysteine by three enzymes in mammalian tissues. An increasing body of evidence suggests the involvement of H2S in different physiological and pathological processes. Recent studies have shown that H2S has the potential to protect the heart against myocardial infarction, arrhythmia, hypertrophy, fibrosis, ischemia-reperfusion injury, and heart failure. Some mechanisms, such as antioxidative action, preservation of mitochondrial function, reduction of apoptosis, anti-inflammatory responses, angiogenic actions, regulation of ion channel, and interaction with NO, could be responsible for the cardioprotective effect of H2S. Although several mechanisms have been identified, there is a need for further research to identify the specific molecular mechanism of cardioprotection in different cardiac diseases. Therefore, insight into the molecular mechanisms underlying H2S action in the heart may promote the understanding of pathophysiology of cardiac diseases and lead to new therapeutic targets based on modulation of H2S production.

Aims: Myocardial infarction (MI) is a leading cause of death globally. MicroRNAs (miRNAs) have been identified as a novel class of MI injury regulators. Hydrogen sulfide (H 2 S) is a gaseous signaling molecule that regulates cardiovascular function. The purpose of this study was to explore the role of the miR-30 family in protecting against MI injury by regulating H 2 S production. Results: The expression of miR-30 family was upregulated in the murine MI model as well as in the primary cardiomyocyte hypoxic model. However, the cystathionine-c-lyase (CSE) expression was significantly decreased. The overexpression of miR-30 family decreased CSE expression, reduced H 2 S production, and then aggravated hypoxic cardiomyocyte injury. In contrast, silencing the whole miR-30 family can protect against hypoxic cell injury by elevating CSE and H 2 S level. Nonetheless, the protective effect was abolished by cotransfecting with CSE-siRNA. Systemic delivery of a locked nucleic acid (LNA)-miR-30 family inhibitor correspondingly increased CSE and H 2 S level, then reduced infarct size, decreased apoptotic cell number in the peri-infarct region, and improved cardiac function in response to MI. However, these cardioprotective effects were absent in CSE knockout mice. MiR-30b overexpression in vivo aggravated MI injury because of H 2 S reduction, and this could be rescued by Spropargyl-cysteine (SPRC), which is a novel modulator of CSE, or further exacerbated by propargylglycine (PAG), which is a selective inhibitor of CSE. Innovation and Conclusion: Our findings reveal a novel molecular mechanism for endogenous H 2 S production in the heart at the miRNA level and demonstrate the therapeutic potential of miR-30 family inhibition for ischemic heart diseases by increasing H 2 S production. Antioxid. Redox Signal. 22,[224][225][226][227][228][229][230][231][232][233][234][235][236][237][238][239][240]

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