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. 2017 Mar 3;120(5):835-847.
doi: 10.1161/CIRCRESAHA.116.309528. Epub 2016 Dec 5.

MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol

Masataka Nishiga  1 , Takahiro Horie  1 , Yasuhide Kuwabara  1 , Kazuya Nagao  1 , Osamu Baba  1 , Tetsushi Nakao  1 , Tomohiro Nishino  1 , Daihiko Hakuno  1 , Yasuhiro Nakashima  1 , Hitoo Nishi  1 , Fumiko Nakazeki  1 , Yuya Ide  1 , Satoshi Koyama  1 , Masahiro Kimura  1 , Ritsuko Hanada  1 , Tomoyuki Nakamura  1 , Tsukasa Inada  1 , Koji Hasegawa  1 , Simon J Conway  1 , Toru Kita  1 , Takeshi Kimura  1 , Koh Ono  2
Affiliations

MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol

Masataka Nishiga et al. Circ Res. .

Abstract

Rationale: Heart failure and atherosclerosis share the underlying mechanisms of chronic inflammation followed by fibrosis. A highly conserved microRNA (miR), miR-33, is considered as a potential therapeutic target for atherosclerosis because it regulates lipid metabolism and inflammation. However, the role of miR-33 in heart failure remains to be elucidated.

Objective: To clarify the role of miR-33 involved in heart failure.

Methods and results: We first investigated the expression levels of miR-33a/b in human cardiac tissue samples with dilated cardiomyopathy. Increased expression of miR-33a was associated with improving hemodynamic parameters. To clarify the role of miR-33 in remodeling hearts, we investigated the responses to pressure overload by transverse aortic constriction in miR-33-deficient (knockout [KO]) mice. When mice were subjected to transverse aortic constriction, miR-33 expression levels were significantly upregulated in wild-type left ventricles. There was no difference in hypertrophic responses between wild-type and miR-33KO hearts, whereas cardiac fibrosis was ameliorated in miR-33KO hearts compared with wild-type hearts. Despite the ameliorated cardiac fibrosis, miR-33KO mice showed impaired systolic function after transverse aortic constriction. We also found that cardiac fibroblasts were mainly responsible for miR-33 expression in the heart. Deficiency of miR-33 impaired cardiac fibroblast proliferation, which was considered to be caused by altered lipid raft cholesterol content. Moreover, cardiac fibroblast-specific miR-33-deficient mice also showed decreased cardiac fibrosis induced by transverse aortic constriction as systemic miR-33KO mice.

Conclusion: Our results demonstrate that miR-33 is involved in cardiac remodeling, and it preserves lipid raft cholesterol content in fibroblasts and maintains adaptive fibrotic responses in the remodeling heart.

Keywords: atherosclerosis; fibroblasts; fibrosis; heart failure; microRNAs.

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