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Sci Rep. 2016 Aug 11;6:30726. doi: 10.1038/srep30726.

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

Author information

1
Biomedical Research Institute, Chonnam National University Hospital, Gwangju, 61469, Republic of Korea.
2
Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju, 61469, Republic of Korea.
3
School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju 61005, Republic of Korea.
4
Department of Cardiology, Chonnam National University Hospital, Gwangju 61469, Republic of Korea.

Abstract

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-3β 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.

PMID:
27510556
PMCID:
PMC4980696
DOI:
10.1038/srep30726
[Indexed for MEDLINE]
Free PMC Article

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