1. Academic Validation
  2. Cardiac-specific CGI-58 deficiency activates the ER stress pathway to promote heart failure in mice

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

  • Cell Death Dis. 2021 Oct 26;12(11):1003. doi: 10.1038/s41419-021-04282-7.
Xin Xie 1 Yi-Fan Tie 1 Song Lai 1 Yun-Long Zhang 2 Hui-Hua Li 3 4 Ying Liu 5
Affiliations

Affiliations

  • 1 Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, 116011, Dalian, China.
  • 2 Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chaoyang Hospital, Capital Medical University, 100020, Beijing, China.
  • 3 Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, 116011, Dalian, China. hhli1935@aliyun.com.
  • 4 Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chaoyang Hospital, Capital Medical University, 100020, Beijing, China. hhli1935@aliyun.com.
  • 5 Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, 116011, Dalian, China. yingliu.med@gmail.com.
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.

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