Genetic deficiency of CCL5 exhibits the phenotypes of HFpEF and aggravates apoptotic cardiomyopathy in HFD-induced diabetic mice

Abstract

The chemokine C-C motif ligand 5 (CCL5) has been implicated in both metabolic dysfunction and cardiovascular diseases; however, its specific role in the pathophysiology of diabetic cardiomyopathy and heart failure remains incompletely understood. This study investigates the impact of CCL5 on the progression of diabetic cardiomyopathy and heart failure. A mouse model of obesity, insulin resistance, and diabetes was established using mice subjected to a high-fat diet (HFD). The genetic deletion of CCL5 was performed to evaluate the consequences of CCL5 deletion on metabolic parameters and cardiac function. CCL5 knockout mice subjected to a 20-week HFD exhibited resistance to metabolic complications, including obesity, hypercholesterolemia, hyperinsulinemia, and insulin resistance. However, CCL5 deletion led to the development of heart failure with preserved ejection fraction (HFpEF), characterized by cardiomyocyte hypertrophy, increased cardiac and plasma ANP and BNP expression, diastolic dysfunction, myocardial fibrosis, inflammation, and apoptosis. Additionally, CCL5 deficiency exacerbated HFD-induced TUNEL signaling and increased the expression of apoptosis-related genes and proteins, contributing to apoptotic cardiomyopathy in HFD-induced diabetic mice. Our findings suggest that physiological levels of CCL5 have a detrimental impact on the metabolic phenotype in DM mice, while simultaneously as a modulator on cardiac remodeling. CCL5 deficiency can lead to the development of HFpEF, suggesting its critical involvement in cardiac remodeling. Despite its dual role, CCL5 appears to play a significant modulator in both cardiac remodeling and diabetic metabolism. Targeting CCL5 may represent a novel therapeutic approach for mitigating metabolic disturbances while preserving cardiac function in diabetic cardiomyopathy. KEY MESSAGES: The physiological levels of CCL5 have a detrimental impact on the systemic metabolism in HFD-induced diabetic mice, while simultaneously representing a modulator on cardiac remodeling. Deficiency of CCL5 exhibits HFpEF phenotypes and aggravates apoptotic cardiomyopathy in DM mice. This article is the first to reveal the dual role of CCL5 in systemic metabolism and cardiac remodeling, and provides valuable insights in diabetic cardiomyopathy and heart failure, potentially informing future therapeutic strategies.

Keywords: Apoptotic cardiomyopathy; CCL5 KO; DM; HFpEF; Obesity.