Natural product derivative BIO promotes recovery after myocardial infarction via unique modulation of the cardiac microenvironment

被引：42

作者：

Kim, Yong Sook ^{[1
]}

Jeong, Hye-yun ^{[2
]}

Kim, Ah Ra ^{[3
]}

Kim, Woong-Hee ^{[3
]}

Cho, Haaglim ^{[3
]}

Um, JungIn ^{[3
]}

Seo, Youngha ^{[3
]}

Kang, Wan Seok ^{[2
]}

Jin, Suk-Won ^{[3
]}

Kim, Min Chul ^{[4
]}

Kim, Yong-Chul ^{[3
]}

Jung, Da-Woon ^{[3
]}

Williams, Darren R. ^{[3
]}

Ahn, Youngkeun ^{[2
,4
]}

机构：

[1] Chonnam Natl Univ Hosp, Inst Biomed Res, Gwangju 61469, South Korea

[2] Chonnam Natl Univ Hosp, Res Lab Cardiovasc Regenerat, Gwangju 61469, South Korea

[3] Gwangju Inst Sci & Technol, Sch Life Sci, 1 Oryong Dong, Gwangju 61005, South Korea

[4] Chonnam Natl Univ Hosp, Dept Cardiol, Gwangju 61469, South Korea

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

关键词：

NITRIC-OXIDE SYNTHASE; FIBROSIS; DYSFUNCTION; INHIBITION; CELLS; HEART; PROLIFERATION; HYPERTROPHY; MACROPHAGES; ACTIVATION;

D O I：

10.1038/srep30726

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

The cardiac microenvironment includes cardiomyocytes, fibroblasts and macrophages, which regulate remodeling after myocardial infarction (MI). Targeting this microenvironment is a novel therapeutic approach for MI. We found that the natural compound derivative, BIO ((2'Z, 3'E)-6-Bromoindirubin-3'-oxime) modulated the cardiac microenvironment to exert a therapeutic effect on MI. Using a series of co-culture studies, BIO induced proliferation in cardiomyocytes and inhibited proliferation in cardiac fibroblasts. BIO produced multiple anti-fibrotic effects in cardiac fibroblasts. In macrophages, BIO inhibited the expression of pro-inflammatory factors. Significantly, BIO modulated the molecular crosstalk between cardiac fibroblasts and differentiating macrophages to induce polarization to the anti-inflammatory M2 phenotype. In the optically transparent zebrafish-based heart failure model, BIO induced cardiomyocyte proliferation and completely recovered survival rate. BIO is a known glycogen synthase kinase-3 beta inhibitor, but these effects could not be recapitulated using the classical inhibitor, lithium chloride; indicating novel therapeutic effects of BIO. We identified the mechanism of BIO as differential modulation of p27 protein expression and potent induction of anti-inflammatory interleukin-10. In a rat MI model, BIO reduced fibrosis and improved cardiac performance. Histological analysis revealed modulation of the cardiac microenvironment by BIO, with increased presence of anti-inflammatory M2 macrophages. Our results demonstrate that BIO produces unique effects in the cardiac microenvironment to promote recovery post-MI.

引用

页数：13

共 48 条

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