Leptin attenuates diabetic cardiomyopathy-induced cardiac remodeling via regulating cGAS/STING signaling and Opa1-mediated mitochondrial fusion

Abstract

Purpose

This investigation seeks to elucidate the contribution of leptin to the pathogenesis of diabetic cardiomyopathy (DCM).

Methods

Mice were rendered diabetic through the administration of streptozotocin (STZ). Leptin was delivered via subcutaneously implanted osmotic pumps. Assessments of cardiac performance, hypertrophy, and fibrosis were conducted using echocardiography, Hematoxylin and Eosin (H&E), Wheat Germ Agglutinin (WGA), and Masson trichrome staining. Myocardial apoptosis and oxidative stress were quantified through TUNEL assay and biochemical markers of oxidative stress, including Malondialdehyde (MDA), 4-Hydroxynonenal (4-HNE), and 3-Nitrotyrosine (3NT). Mitochondrial structure was examined using Transmission Electron Microscopy (TEM). Primary neonatal cardiomyocytes were subjected to high glucose (HG) conditions. The fluorescent indicators MitoTracker Green and MitoSOX Red were employed to evaluate mitochondrial morphology and function within the cardiomyocytes.

Results

Mice with diabetes displayed marked cardiac hypertrophy and fibrosis, as indicated by H&E, WGA, and Masson staining. The administration of leptin significantly mitigated the cardiac pathological manifestations in diabetic mice. Leptin increased the expression of Opa1 and enhanced mitochondrial fusion and function in cardiomyocytes exposed to HG. The cGAS/STING signaling pathway may serve as a pivotal intermediary for leptin to facilitate Opa1-driven mitochondrial fusion.

Conclusions

Leptin appears to safeguard against hyperglycemia-induced mitochondrial oxidative damage and DCM by modulating the cGAS/STING signaling cascade and Opa1-mediated mitochondrial fusion. These results propose that leptin could be a promising agent for promoting mitochondrial fusion and preventing diabetes-associated cardiac pathologies.