Key result
mTOR inhibition attenuates ischemia-reperfusion injury in diabetic myocardium by restoring impaired autophagic flux.
Why the study?
The increased myocardial vulnerability following ischemia-reperfusion injury in diabetic patients is a significant perioperative risk, and the intrinsic mechanisms underlying this phenomenon require comprehensive understanding.
Inhibition of mTOR during hypoxia/reoxygenation injury restores RILP expression and attenuates cellular injury in cardiomyocytes cultured with high glucose, suggesting a potential cardioprotective mechanism for diabetic myocardium.
Impaired autophagic flux may heighten perioperative I/RI risk in diabetes; leaves open whether mTOR/RILP modulation translates to clinical cardioprotection.
Background: The increased myocardial vulnerability that occurs in diabetic patients following an ischemia-reperfusion injury (I/RI) represents a significant perioperative safety risk. A comprehensive understanding of the intrinsic mechanisms underlying this phenomenon is therefore of paramount importance. Purposes: The objective of this study is to investigate the potential mechanism of action between impaired autophagic flux and increased vulnerability in diabetic myocardium. This will provide a foundation for the clinical search for effective preventive and curative measures. Methods: The transcriptomic alterations in autophagy-related genes following myocardial exposure to I/RI were analyzed by single-cell sequencing. This was followed by the validation of potential mechanisms of action between impaired autophagic flux and increased susceptibility at the cellular and animal levels, respectively. Results: After I/RI in diabetic myocardium, there was a significant increase in the number of CM1 subgroups and a specific downregulation of 239 autophagy-related genes led by RILP. HE staining revealed that myocardial injury was exacerbated in diabetic mice subjected to I/RI. Transmission electron microscopy revealed that the accumulation of autophagic vesicles in cardiomyocytes of diabetic mice resulted in impaired autophagic flux. qRT-PCR revealed that the expression of RILP was significantly reduced in diabetic mice subjected to I/RI. WB showed that P62 was significantly increased and RILP was significantly decreased in diabetic mice subjected to I/RI compared to healthy mice. Inhibition of mTOR during hypoxia/reoxygenation (H/R) injury restored RILP expression and attenuated cellular injury in cardiomyocytes cultured with high glucose. Conclusion: Following I/RI in diabetic myocardium, an increase in the CM1 subpopulation and a reduction in RILP expression result in impaired autophagic flux. Regulation of the mTOR/RILP pathway can restore impaired autophagic flux and improve myocardial vulnerability, thereby exerting cardioprotective effects.
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Zhao et al. (2025) studied Myocardial ischemia-reperfusion injury in diabetes. mTOR inhibition (Rapamycin) vs. High-glycemic hypoxia/reoxygenation without intervention was evaluated on Autophagic flux and cellular injury (apoptosis and survival). Following ischemia-reperfusion injury in diabetic myocardium, reduced RILP expression impairs autophagic flux, which can be restored by mTOR inhibition to attenuate myocardial injury.
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