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Published on: September 24, 2020
Sevoflurane Alleviates Myocardial Ischemia/Reperfusion Injury Via Regulating TRIM65-Mediated Ubiquitination
Yunling Deng1, Panguo Rao1, Yuxuan Liu1
1Department of Anesthesiology, First Affiliated Hospital of Gannan Medical University, Shuiyun Jiacheng, Ganzhou, Jiangxi Province, 341000, China.
Abstract:
Background As a commonly used anesthetic in clinical practice, sevoflurane (Sevo) has been found to have a certain protective effect on myocardial ischemia/reperfusion (MI/R) injury. However, the underlying molecular mechanisms deserve further elucidation. Methods Human cardiomyocytes were induced by hypoxia/reoxygenation (H/R), and MI/R rat model was established by ligation of left coronary artery. Cell viability and apoptosis were tested using CCK8 assay and flow cytometry. Inflammatory factors and ferroptosis-related markers were tested by corresponding kit. The levels of ALOX5, ferroptosis-related markers, and tripartite motif 65 (TRIM65) were determined by qRT-PCR or western blot. The interaction between TRIM65 and ALOX5 was evaluated by Co-IP assay. Results Sevo repressed H/R-induced cardiomyocyte apoptosis, inflammation, and ferroptosis. Sevo reduced the ALOX5 protein level, and ALOX5 overexpression reversed the inhibitory effects of Sevo on H/R-induced cardiomyocyte injury. E3 ubiquitin ligase TRIM65 could decrease ALOX5 protein stability by promoting its ubiquitination level. TRIM65 inhibited H/R-induced cardiomyocyte apoptosis, inflammation, and ferroptosis by downregulating ALOX5. Furthermore, TRIM65 knockdown reversed the protective effects of Sevo on H/R-induced cardiomyocyte injury. Additionally, Sevo alleviated MI/R injury in rat models by activating TRIM65-mediated ubiquitination of ALOX5. Conclusion Sevo restrained H/R-induced cardiomyocyte apoptosis, inflammation, and ferroptosis to alleviate MI/R injury, which might be associated with the TRIM65/ALOX5 axis.
Insights
Sevoflurane protects against myocardial ischemia/reperfusion (MI/R) injury by inhibiting cardiomyocyte apoptosis, inflammation, and ferroptosis. This effect is mediated by the TRIM65/ALOX5 axis, highlighting a novel therapeutic mechanism.
Area of Science:
- Cardiology
- Anesthesiology
- Molecular Biology
Background:
- Sevoflurane (Sevo) is a widely used anesthetic with known protective effects against myocardial ischemia/reperfusion (MI/R) injury.
- The precise molecular mechanisms underlying sevoflurane's cardioprotective actions require further investigation.
Purpose of the Study:
- To elucidate the molecular mechanisms by which sevoflurane mitigates MI/R injury.
- To investigate the role of the TRIM65/ALOX5 axis in sevoflurane's protective effects.
Main Methods:
- Hypoxia/reoxygenation (H/R) was used to induce injury in human cardiomyocytes.
- A rat model of MI/R was established.
- Cell viability, apoptosis, inflammatory factors, and ferroptosis markers were assessed.
- Quantitative real-time PCR (qRT-PCR), western blot, and co-immunoprecipitation (Co-IP) assays were employed to analyze protein levels and interactions.
Main Results:
- Sevoflurane significantly repressed H/R-induced cardiomyocyte apoptosis, inflammation, and ferroptosis.
- Sevoflurane reduced ALOX5 protein levels; ALOX5 overexpression counteracted sevoflurane's protective effects.
- E3 ubiquitin ligase TRIM65 was found to decrease ALOX5 protein stability via ubiquitination.
- TRIM65 activation by sevoflurane inhibited cardiomyocyte injury by downregulating ALOX5, an effect reversed by TRIM65 knockdown.
Conclusions:
- Sevoflurane alleviates MI/R injury by suppressing cardiomyocyte apoptosis, inflammation, and ferroptosis.
- The protective effects of sevoflurane are associated with the activation of the TRIM65/ALOX5 axis, involving TRIM65-mediated ALOX5 ubiquitination.
