Jiung-Pang Huang1, Mei-Ling Cheng2, Chao-Hung Wang3, Shiang-Suo Huang4, Po-Shiuan Hsieh5, Chih-Chun Chang6, Chao-Yu Kuo7, Kuan-Hsing Chen8, Li-Man Hung9. 1. Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan. Electronic address: dddivekimo@yahoo.com.tw. 2. Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan. Electronic address: chengm@mail.cgu.edu.tw. 3. Heart Failure Center, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan. Electronic address: bearty@adm.cgmh.org.tw. 4. Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan. Electronic address: sshuang@csmu.edu.tw. 5. Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan. Electronic address: pshsieh@hotmail.com. 6. Department of Clinical Pathology, Far Eastern Memorial Hospital, New Taipei, Taiwan. Electronic address: chihchun.chang1211@gmail.com. 7. Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address: as22340@hotmail.com. 8. Kidney Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan. Electronic address: guanhsing@yahoo.com.tw. 9. Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Kidney Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan; Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan. Electronic address: lisahung@mail.cgu.edu.tw.
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.
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 humanpatients. 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 humanpatients. 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.