Abstract
Background: Lipid expression is increased in the atrial myocytes of mitral regurgitation (MR) patients. This study aimed to investigate key regulatory genes and mechanisms of atrial lipotoxic myopathy in MR. Methods: The HL-1 atrial myocytes were subjected to uniaxial cyclic stretching for eight hours. Fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism were analyzed by PCR assay (168 genes). Results: The stretched myocytes had significantly larger cell size and higher lipid expression than non-stretched myocytes (all p < 0.001). Fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism in the myocytes were analyzed by PCR assay (168 genes). In comparison with their counterparts in non-stretched myocytes, seven genes in stretched monocytes (Idi1, Olr1, Nr1h4, Fabp2, Prkag3, Slc27a5, Fabp6) revealed differential upregulation with an altered fold change >1.5. Nine genes in stretched monocytes (Apoa4, Hmgcs2, Apol8, Srebf1, Acsm4, Fabp1, Acox2, Acsl6, Gk) revealed differential downregulation with an altered fold change <0.67. Canonical pathway analysis, using Ingenuity Pathway Analysis software, revealed that the only genes in the “superpathway of cholesterol biosynthesis” were Idi1 (upregulated) and Hmgcs2 (downregulated). The fraction of stretched myocytes expressing Nile red was significantly decreased by RNA interference of Idi1 (p < 0.05) and was significantly decreased by plasmid transfection of Hmgcs2 (p = 0.004). Conclusions: The Idi1 and Hmgcs2 genes have regulatory roles in atrial lipotoxic myopathy associated with atrial enlargement.
Highlights
Mitral regurgitation (MR) is an important valve disease related to heart failure [1]
Expressions of genes linked to the peroxisome proliferator-activated receptors (PPARs) signaling pathway, especially genes related to fatty acid β-oxidation, in the left atria of mitral regurgitation (MR) patients reportedly differs from patients with aortic valve disease and normal controls [14]
In a novel mouse model of lipotoxic cardiomyopathy, Chiu et al showed that a fatty acid uptake–utilization mismatch in the heart causes lipid accumulation, which is associated with initial cardiac hypertrophy, followed by the development of myocardial dysfunction and cardiac myocyte death, which is partly caused by lipid-induced programmed cell death [12]
Summary
Mitral regurgitation (MR) is an important valve disease related to heart failure [1]. Expressions of genes linked to the PPAR signaling pathway, especially genes related to fatty acid β-oxidation, in the left atria of MR patients reportedly differs from patients with aortic valve disease and normal controls [14]. Mitral regurgitation patients have significantly higher lipid expression of atrial myocytes compared to normal controls [14]. Lipoprotein signaling, and cholesterol metabolism were analyzed by PCR assay (168 genes). Lipoprotein signaling, and cholesterol metabolism in the myocytes were analyzed by PCR assay (168 genes). In comparison with their counterparts in non-stretched myocytes, seven genes in stretched monocytes (Idi, Olr, Nr1h4, Fabp, Prkag, Slc27a5, Fabp6) revealed differential upregulation with an altered fold change >1.5. Conclusions: The Idi and Hmgcs genes have regulatory roles in atrial lipotoxic myopathy associated with atrial enlargement
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