Masataka Nishiga1, Takahiro Horie1, Yasuhide Kuwabara1, Kazuya Nagao1, Osamu Baba1, Tetsushi Nakao1, Tomohiro Nishino1, Daihiko Hakuno1, Yasuhiro Nakashima1, Hitoo Nishi1, Fumiko Nakazeki1, Yuya Ide1, Satoshi Koyama1, Masahiro Kimura1, Ritsuko Hanada1, Tomoyuki Nakamura1, Tsukasa Inada1, Koji Hasegawa1, Simon J Conway1, Toru Kita1, Takeshi Kimura1, Koh Ono2. 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.
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.
Authors: Nathan L Price; Verónica Miguel; Wen Ding; Abhishek K Singh; Shipra Malik; Noemi Rotllan; Anna Moshnikova; Jakub Toczek; Caroline Zeiss; Mehran M Sadeghi; Noemi Arias; Ángel Baldán; Oleg A Andreev; Diego Rodríguez-Puyol; Raman Bahal; Yana K Reshetnyak; Yajaira Suárez; Carlos Fernández-Hernando; Santiago Lamas Journal: JCI Insight Date: 2019-11-14
Authors: Pedro H D M Prazeres; Anaelise O M Turquetti; Patrick O Azevedo; Rodrigo S N Barreto; Maria A Miglino; Akiva Mintz; Osvaldo Delbono; Alexander Birbrair Journal: Int J Biochem Cell Biol Date: 2018-04-05 Impact factor: 5.085
Authors: Nathan L Price; Xinbo Zhang; Pablo Fernández-Tussy; Abhishek K Singh; Sean A Burnap; Noemi Rotllan; Leigh Goedeke; Jonathan Sun; Alberto Canfrán-Duque; Binod Aryal; Manuel Mayr; Yajaira Suárez; Carlos Fernández-Hernando Journal: Proc Natl Acad Sci U S A Date: 2021-02-02 Impact factor: 11.205