Novel Mechanism of SIRT3 Regulation in Cardiac Inflammatory Injury: The Key Role of MITOL

Abstract

Background: Myocardial injury is a common heart disease that involves various forms of cell death, including pyroptosis. Lipopolysaccharide (LPS) can simulate the inflammatory response of cardiomyocytes, resulting in their damage. Sirtuin 3 (SIRT3), a mitochondrial deacetylase, has been shown to play a role in cardiac protection. This study aimed to investigate whether SIRT3 mitigates inflammation-induced cardiomyocyte pyroptosis and alleviates LPS-induced myocardial injury via the mitochondrial ubiquitin ligase (MITOL)-dependent mechanism. Methods: Mouse and H9C2 cardiomyocyte models were used to simulate myocardial inflammatory injury by LPS treatment. Cardiac ultrasound, protein expression analysis, mRNA expression detection, and serum biochemical indicators were used to assess the extent of myocardial injury. The EdU experiment was conducted to detect cell proliferation capacity. DCFH-DA fluorescence was used to measure Reactive Oxygen Species (ROS) levels. JC-1 probe analysis was used to assess the aggregate/monomer ratio in different treatment groups. Furthermore, SIRT3 treatment and MITOL silencing experiments were conducted to explore the impact of SIRT3 on cardiomyocyte pyroptosis and whether it functions through MITOL. Scanning electron microscopy experiments were conducted to assess the reversal of the protective effect of SIRT3 by silencing MITOL. Results: The experimental results showed that LPS treatment significantly impaired mouse cardiac function, increased the expression of pyroptosis-related proteins in cardiomyocytes, elevated serum myocardial injury indicators, and increased the mRNA expression of inflammatory factors (tumor necrosis factor-alpha (TNFα) and interleukin-1β (IL-1β)). SIRT3 treatment significantly reduced LPS-induced myocardial injury, improved cardiac function, reduced the expression of pyroptosis-related proteins, and decreased inflammatory factors. Silencing MITOL reversed the protective effect of SIRT3 on cardiomyocyte injury, suggesting that SIRT3 exerted its therapeutic effect through MITOL. Conclusion: This study revealed that SIRT3 mitigated inflammation-induced cardiomyocyte pyroptosis via a MITOL-dependent mechanism, thereby alleviating LPS-induced myocardial injury. This finding provides a new molecular target for the treatment of myocardial inflammation-related diseases and lays a theoretical foundation for the development of cardiac protection strategies. Future research can further explore the potential application of the SIRT3-MITOL axis in cardiac diseases, providing effective treatment methods for cardiac patients.