Cardiac-specific CGI-58 deficiency activates the ER stress pathway to promote heart failure in mice

Xin Xie,Yun-Long Zhang,Hui-Hua Li,Ying Liu,Song Lai,Yi-Fan Tie

doi:10.1038/s41419-021-04282-7

Abstract

Excess myocardial triacylglycerol accumulation (i.e., cardiac steatosis) impairs heart function, suggesting that enzymes promoting triacylglycerol metabolism exert essential regulatory effects on heart function. Comparative gene identification 58 (CGI-58) is a key enzyme that promotes the hydrolysis of triglycerides by activating adipose triglyceride lipase and plays a protective role in maintaining heart function. In this study, the effects of CGI-58 on heart function and the underlying mechanism were investigated using cardiac-specific CGI58-knockout mice (CGI-58cko mice). Echocardiography and pathological staining were performed to detect changes in the structure and function of the heart. Proteomic profiling, immunofluorescent staining, western blotting, and real-time PCR were used to evaluate molecular changes. In CGI-58cko mice, we detected cardiac hypertrophic remodeling and heart failure associated with excessive cardiac lipid accumulation, ROS production, and decreased expression of regulators of fatty acid metabolism. These changes were markedly attenuated in CGI-58cko mice injected with rAAV9-CGI58. A quantitative proteomics analysis revealed significant increases in the expression of ER stress-related proteins and decreases in proteins related to fatty acid and amino acid metabolism in the hearts of CGI-58cko mice. Furthermore, the inhibition of ER stress by the inhibitor 4-PBA improved mitochondrial dysfunction, reduced oxidative stress, and reversed cardiac remodeling and dysfunction in cultured cardiomyocytes or in CGI-58cko mice. Our results suggested that CGI-58 is essential for the maintenance of heart function by reducing lipid accumulation and ER stress in cardiomyocytes, providing a new therapeutic target for cardiac steatosis and dysfunction.

Highlights

Cardiac energy metabolism is correlated with cardiac function and plays a critical role in the pathogenesis of heart failure (HF) [1]
Comparative gene identification 58 (CGI-58) deficiency in cardiomyocytes induces cardiac remodeling and dysfunction in mice fed a ND and high-fat diet (HFD) To investigate whether CGI-58 regulates heart function, we selectively reduced CGI-58 expression in cardiomyocytes of mice using the Cre-LoxP system and confirmed the downregulation of CGI-58 expression in the heart by immunoblotting (Supplemental Fig. 1)
CGI-58cko mice showed a significant decrease in left ventricular (LV) contractile function, as indicated by a decreased LV EF% and FS% compared with those in CGI-58f/f mice under ND conditions (Fig. 1C)

Summary

Introduction

Cardiac energy metabolism is correlated with cardiac function and plays a critical role in the pathogenesis of heart failure (HF) [1]. The impairment of FA metabolism leads to cardiac dysfunction. Previous studies have revealed that myocardial TG accumulation is closely associated with cardiac myocyte apoptosis and contractile dysfunction in rodents and humans under different pathological conditions, such as ischemia and pressure overload [3,4,5]. Recent studies have verified that endoplasmic reticulum (ER) stress activation mediates lipid-driven cardiac dysfunction [6, 7]. ER stress frequently impairs mitochondrial function and reduces energy expenditure, leading to cardiomyocyte apoptosis in hypertrophic or failing hearts after pressure overload or ischemic injury [9,10,11,12]. The causal relationship between lipid accumulation-induced ER stress and cardiac dysfunction is not clearly established

Results

Discussion

Conclusion