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Circ Res. 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.

Author information

1
From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
2
From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita). kohono@kuhp.kyoto-u.ac.jp.

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

PMID:
27920122
DOI:
10.1161/CIRCRESAHA.116.309528
[Indexed for MEDLINE]

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