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

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

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)835-847
Number of pages13
JournalCirculation Research
Volume120
Issue number5
DOIs
StatePublished - Mar 3 2017

Fingerprint

MicroRNAs
Cholesterol
Lipids
Constriction
Fibrosis
Fibroblasts
Heart Failure
Atherosclerosis
Inflammation
Dilated Cardiomyopathy
Lipid Metabolism
Knockout Mice
Heart Ventricles

Keywords

  • atherosclerosis
  • fibroblasts
  • fibrosis
  • heart failure
  • microRNAs

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol. / Nishiga, Masataka; Horie, Takahiro; Kuwabara, Yasuhide; Nagao, Kazuya; Baba, Osamu; Nakao, Tetsushi; Nishino, Tomohiro; Hakuno, Daihiko; Nakashima, Yasuhiro; Nishi, Hitoo; Nakazeki, Fumiko; Ide, Yuya; Koyama, Satoshi; Kimura, Masahiro; Hanada, Ritsuko; Nakamura, Tomoyuki; Inada, Tsukasa; Hasegawa, Koji; Conway, Simon; Kita, Toru; Kimura, Takeshi; Ono, Koh.

In: Circulation Research, Vol. 120, No. 5, 03.03.2017, p. 835-847.

Research output: Contribution to journalArticle

Nishiga, M, Horie, T, Kuwabara, Y, Nagao, K, Baba, O, Nakao, T, Nishino, T, Hakuno, D, Nakashima, Y, Nishi, H, Nakazeki, F, Ide, Y, Koyama, S, Kimura, M, Hanada, R, Nakamura, T, Inada, T, Hasegawa, K, Conway, S, Kita, T, Kimura, T & Ono, K 2017, 'MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol', Circulation Research, vol. 120, no. 5, pp. 835-847. https://doi.org/10.1161/CIRCRESAHA.116.309528
Nishiga, Masataka ; Horie, Takahiro ; Kuwabara, Yasuhide ; Nagao, Kazuya ; Baba, Osamu ; Nakao, Tetsushi ; Nishino, Tomohiro ; Hakuno, Daihiko ; Nakashima, Yasuhiro ; Nishi, Hitoo ; Nakazeki, Fumiko ; Ide, Yuya ; Koyama, Satoshi ; Kimura, Masahiro ; Hanada, Ritsuko ; Nakamura, Tomoyuki ; Inada, Tsukasa ; Hasegawa, Koji ; Conway, Simon ; Kita, Toru ; Kimura, Takeshi ; Ono, Koh. / MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol. In: Circulation Research. 2017 ; Vol. 120, No. 5. pp. 835-847.
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AU - Nishiga, Masataka

AU - Horie, Takahiro

AU - Kuwabara, Yasuhide

AU - Nagao, Kazuya

AU - Baba, Osamu

AU - Nakao, Tetsushi

AU - Nishino, Tomohiro

AU - Hakuno, Daihiko

AU - Nakashima, Yasuhiro

AU - Nishi, Hitoo

AU - Nakazeki, Fumiko

AU - Ide, Yuya

AU - Koyama, Satoshi

AU - Kimura, Masahiro

AU - Hanada, Ritsuko

AU - Nakamura, Tomoyuki

AU - Inada, Tsukasa

AU - Hasegawa, Koji

AU - Conway, Simon

AU - Kita, Toru

AU - Kimura, Takeshi

AU - Ono, Koh

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N2 - 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.

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KW - atherosclerosis

KW - fibroblasts

KW - fibrosis

KW - heart failure

KW - microRNAs

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