Metformin Alleviates Sepsis-Associated Myocardial Injury by Enhancing AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Signaling Pathway-Mediated Autophagy.

Abstract

ABSTRACT:

Sepsis-associated myocardial injury is one of the main causes of death in intensive care units, and current clinical treatments have not been satisfactory. Therefore, finding an effective intervention is an urgent requirement. Metformin, an anti-type 2 diabetes drug, has been reported to be an autophagic activator agent that confers protection in some diseases. However, it is unclear whether it can provide defense against sepsis-associated myocardial injury. In this study, we investigated the cardioprotective effects of metformin pretreatment against lipopolysaccharide (LPS)-induced myocardial injury in C57BL/6J mice or H9c2 cells and the possible underlying mechanisms. Metformin was administered at a dose of 100 mg/kg for a week before LPS intraperitoneal injection. Twenty-four hours after LPS intervention, echocardiographic evaluation, reactive oxygen species measurement, Hoechst staining, western blotting, hematoxylin and eosin staining, and enzyme-linked immunosorbent assay were performed. Inhibitors of autophagy and AMP-activated protein kinase (AMPK) were used to further clarify the mechanisms involved. Metformin pretreatment effectively attenuated cardiac dysfunction, reduced the levels of myocardial enzymes, and alleviated cardiac hydroncus in LPS-treated mice. In addition, metformin restored the LPS-disrupted antioxidant defense and activated LPS-reduced autophagy by modulating the AMPK/mammalian target of rapamycin (AMPK/mTOR) pathway both in vivo and in vitro. The antioxidant effects of metformin on cardiomyocytes were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Treatment with compound C, an AMPK inhibitor, reversed the metformin-induced autophagy in LPS-treated H9c2 cells. In conclusion, metformin pretreatment alleviates LPS-induced myocardial injury by activating AMPK/mTOR pathway-mediated autophagy.

• Authors: Yu Gao, Jiao Liu, Kemin Li, Tian Li, Ruihan Li, Wenlong Zhang, Xuanping Zhang, Yan Wang, Min Chen, Ruizan Shi, Jing Cao
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 82 Issue 4 Pg. 308-317 (10 01 2023) ISSN: 1533-4023 [Electronic] United States
• PMID: 37499052 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.

Chemical References

• AMP-Activated Protein Kinases
• Metformin
• Sirolimus
• Lipopolysaccharides
• TOR Serine-Threonine Kinases

Topics

• Mice
• Animals
• AMP-Activated Protein Kinases (metabolism)
• Metformin (pharmacology, therapeutic use)
• Sirolimus (pharmacology)
• Lipopolysaccharides (toxicity)
• Mice, Inbred C57BL
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)
• Autophagy
• Sepsis (complications, drug therapy)
• Mammals (metabolism)