Abstract 17310: MicroRNA-33 Maintains Cellular Cholesterol Content in Fibroblasts and Fibrotic Response in Heart
Introduction: Heart failure and atherosclerosis share the underlying mechanisms of chronic inflammation followed by fibrosis. A highly conserved microRNA, miR-33 is considered as a potential therapeutic target for atherosclerosis because it regulates lipid metabolism and inflammation. However, the functions of miR-33 in heart failure remain to be elucidated.
Objective: To clarify the functions of miR-33 involved in pathological cardiac remodeling.
Methods and Results: We first investigated the expression levels of miR-33a/b in human cardiac tissue samples with dilated cardiomyopathy. Expression of miR-33a was associated with improving hemodynamic parameters. To clarify the function of miR-33 in remodeling heart, we investigated the responses to pressure overload by transverse aortic constriction (TAC) in miR-33 deficient (KO) mice. When mice were subjected to TAC, miR-33 expression level was significantly up-regulated in wild-type (WT) left ventricles. There was no difference in hypertrophic responses between WT hearts and miR-33KO hearts. However, interestingly, histological and gene expression analyses showed ameliorated cardiac fibrosis in miR-33KO hearts compared with that in WT hearts. We also found that cardiac fibroblasts were mainly responsible for miR-33 expression in the heart. Deficiency of miR-33 impaired cell proliferation in fibroblasts, which was considered due to altered lipid raft cholesterol content by up-regulated genes involved in cholesterol metabolism. To examine miR-33 function in cardiac fibroblasts in vivo, we generated cardiac fibroblast-specific miR-33 deficient mice, which also showed ameliorated cardiac fibrosis when they were subjected to TAC as global miR-33KO mice.
Conclusions: Our results demonstrate that miR-33 is involved in cardiac remodeling and it maintains cellular cholesterol content in fibroblasts and fibrotic response in heart.
Author Disclosures: M. Nishiga: None. T. Horie: None. Y. Kuwabara: None. O. Baba: None. T. Nakao: None. T. Nishino: None. D. Hakuno: None. Y. Nakashima: None. K. Nagao: None. K. Hasegawa: None. T. Kita: None. T. Kimura: None. K. Ono: None.
- © 2016 by American Heart Association, Inc.