Mechanism Study Of Comparative Gene Identification-58(CGI-58) In Triglyceride Metabolism And Heart Failure

Background and Objective:Heart failure is the leading cause of death in cardiovascular diseases.About 60%-80%of the energy supply for the heart is from fatty acid oxidation.Under the normal condition,fatty acid synthesis and metabolism are balanced and precisely regu-lated.However,in the setting of heart failure,the lipid metabolism of cardiomyocytes is irregulated and might contributed to the progression of the heart faliure.Recent studies show that comparative gene identification-58(CGI-58)(also known as alpha/beta hy-drolase domain-5(Abhd-5))plays a positive protective role in the progress of fat me-tabolism.CGI-58 is a co-activator of ATGL(Adipose triglyceride lipase),which en-hances hydrolase activity after binding with ATGL.However,the mechanisms whereby lipid metabolism in heart failure remains incompletely understood.In the present study,we used cardiac-CGI-58 conditional knockout mice to investigate the role of CGI-58 in transverse aortic constriction(TAC)-induced heart failure.Materials and methods:Patients with heart failure(1101)were randomly enrolled in our study.Clinical examinations included a 12-lead ECG,blood lipid levels and detailed history of medica-tions was recorded.We used 8-week-old male cardiac-CGI-58 conditional knockout mice and wild type(WT)mice to induce TAC and sham operation.A Vevo 770 High-Resolution Imaging System was used to measure the cardiac function.Left ven-tricular anterior wall thickness,left ventricular back wall thickness,left ventricular sys-tolic and end-diastolic volume were recorded and used to calculate left ventricular ejec-tion fraction(EF%)and fractional shortening(FS%).Cardiac inflammation was as-sessed by hematoxylin and eosin(H&E)staining,Mac-2 staining and the m RNA levels of IL-1,IL-6 and TNF-a.WGA staining and mRNA levels of ANP,BNP and Myh-7 in heart tissues were used to evaluate cardiac hypertrophy.Heart fibrosis was examined by Masson staining and the levels of collagen I&III.Oil-red O staining,and mRNA levels of ATGL,PPAR-alpha,PGC-1,ATP syn and LPL was used to measure the lipid deposi-tion in cardiomyocytes.In addition,we measured the triglyceride and cholesterol levels in the hearts of mice.Results:1)About 30%of heart failure patients had high lipid levels;2)under the condition of TAC,cardiac function in cCgi58 knockout mice was decreased more significantly than wild type group;3)compared with wild type,the extent of inflammatory responses,cardiac hypertrophy and fibrosis were significantly up-regulated in cCgi58 knockout mice;4)the lipid deposition is dramatically increased in cCgi58 knockout mice as comparied with wild type.Conclusion:In the setting of pressure-over load,cardiac-derived CGI-58 limited heart hyper-trophy,inflammatory responses and fibrosis by promoting lipid degradation,which dis-played a protective role in the progression of heart failure.