Chronic Pharmacological Modulation of Mitochondrial Dynamics Alleviates Prediabetes-Induced Myocardial Ischemia-Reperfusion Injury by Preventing Mitochondrial Dysfunction and Programmed Apoptosis.

Abstract

PURPOSE:

There is an increasing body of evidence to show that impairment in mitochondrial dynamics including excessive fission and insufficient fusion has been observed in the pre-diabetic condition. In pre-diabetic rats with cardiac ischemia-reperfusion (I/R) injury, acute treatment with a mitochondria fission inhibitor (Mdivi-1) and a fusion promoter (M1) showed cardioprotection. However, the potential preventive effects of chronic Mdivi-1 and M1 treatment in a pre-diabetic model of cardiac I/R have never been elucidated.

METHODS:

Male Wistar rats (n = 40) were fed with a high-fat diet (HFD) for 12 weeks to induce prediabetes. Then, all pre-diabetic rats received the following treatments daily via intraperitoneal injection for 2 weeks: (1) HFDV (Vehicle, 0.1% DMSO); (2) HFMdivi1 (Mdivi-1 1.2 mg/kg); (3) HFM1 (M1 2 mg/kg); and (4) HFCom (Mdivi-1 + M1). At the end of treatment protocols, all rats underwent 30 min of coronary artery ligation followed by reperfusion for 120 min.

RESULTS:

Chronic Mdivi-1, M1, and the combined treatment showed markedly improved cardiac mitochondrial function and dynamic control, leading to a decrease in cardiac arrhythmias, myocardial cell death, and infarct size (49%, 42%, and 51% reduction for HFMdivi1, HFM1, and HFCom, respectively vs HFDV). All of these treatments improved cardiac function following cardiac I/R injury in pre-diabetic rats.

CONCLUSION:

Chronic inhibition of mitochondrial fission and promotion of fusion exerted cardioprevention in prediabetes with cardiac I/R injury through the relief of cardiac mitochondrial dysfunction and dynamic alterations, and reduction in myocardial infarction, thus improving cardiac function.

• Authors: Chayodom Maneechote, Sasiwan Kerdphoo, Thidarat Jaiwongkam, Siriporn C Chattipakorn, Nipon Chattipakorn
• Journal: Cardiovascular drugs and therapy (Cardiovasc Drugs Ther) Vol. 37 Issue 1 Pg. 89-105 (02 2023) ISSN: 1573-7241 [Electronic] United States
• PMID: 34515894 (Publication Type: Journal Article)
• Copyright: © 2021. Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Mdivi-1

Topics

• Rats
• Male
• Animals
• Myocardial Reperfusion Injury (drug therapy, prevention & control, metabolism)
• Rats, Wistar
• Mitochondrial Dynamics
• Prediabetic State (drug therapy)
• Diabetes Mellitus, Experimental (metabolism)
• Myocytes, Cardiac
• Mitochondria (metabolism)
• Apoptosis