Therapeutic potential of cPLA2 inhibitor to counteract dilated-cardiomyopathy in cholesterol-treated H9C2 cardiomyocyte and MUNO rat. (October 2020)

• Record Type: Journal Article
• Authors: Huang, Jiung-Pang; Cheng, Mei-Ling; Wang, Chao-Hung; Huang, Shiang-Suo; Hsieh, Po-Shiuan; Chang, Chih-Chun; Kuo, Chao-Yu; Chen, Kuan-Hsing; Hung, Li-Man
• Is Part Of: Pharmacological research. Volume 160(2020)
• Publication Date: 2020-10
• Subjects: MUNO metabolically unhealthy nonobesity -- MUO metabolically unhealthy obesity -- HF heart failure -- PCs phosphatidylcholines -- LysoPCs lysophosphatidylcholines -- DCM dilated cardiomyopathy -- cPLA2 cytosolic phospholipase A2 -- MS metabolic syndrome -- TG triglyceride -- FFA free fatty acids -- NEFA nonesterified fatty acid -- HDL high-density lipoprotein -- MBP mean blood pressure -- EHC euglycemic–hyperinsulinemic clamp -- ROS reactive oxygen species -- Ea arterial elastance -- VIP variable importance in projection -- ANF atrial natriuretic factor -- BNP brain natriuretic peptide -- DSP desmoplakin; LysoPC -- Non-obese metabolic syndrome -- Dilated cardiomyopathy -- cPLA2 -- Mitochondria; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.105201
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Background and purpose: The pathogenesis of cardiomyopathy in metabolically unhealthy obesity (MUO) has been well studied. However, the pathogenesis of cardiomyopathy typically associated with high cholesterol levels in metabolically unhealthy nonobesity (MUNO) remains unclear. We investigated whether cholesterol-generated LysoPCs contribute to cardiomyopathy and the role of cytosolic phospholipase A2 (cPLA2) inhibitor in cholesterol-induced MUNO. Experimental approach: Cholesterol diet was performed in Sprague–Dawley rats that were fed either regular chow (C), or high cholesterol chow (HC), or HC diet with 10 % fructose in drinking water (HCF) for 12 weeks. LysoPCs levels were subsequently measured in rats and in MUNO human patients. The effects of cholesterol-mediated LysoPCs on cardiac injury, and the action of cPLA2 inhibitor, AACOCF3, were further assessed in H9C2 cardiomyocytes. Key results: HC and HCF rats fed cholesterol diets demonstrated a MUNO-phenotype and cholesterol-induced dilated cardiomyopathy (DCM). Upregulated levels of LysoPCs were found in rat myocardium and the plasma in MUNO human patients. Further testing in H9C2 cardiomyocytes revealed that cholesterol-induced atrophy and death of cardiomyocytes was due to mitochondrial dysfunction and conditions favoring DCM (i.e. reduced mRNA expression of ANF, BNP, DSP, and atrogin-1), and that AACOCF3 counteracted the cholesterol-induced DCM phenotype. Conclusion and implications: Cholesterol-induced MUNO-DCM phenotype was counteracted by cPLA2 inhibitor, which is potentially useful for the treatment of LysoPCs-associated DCM in MUNO.