title: Natural product derivative BIO promotes recovery after myocardial infarction via unique modulation of the cardiac microenvironment.
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.
authors: Biomedical Research Institute, Chonnam National University Hospital, Gwangju, 61469, Republic of Korea.
authors: Yong Sook
authors: YS
authors: Kim
authors: Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju, 61469, Republic of Korea.
authors: Hye-Yun
authors: HY
authors: Jeong
authors: School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju 61005, Republic of Korea.
authors: Ah Ra
authors: AR
authors: Kim
authors: School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju 61005, Republic of Korea.
authors: Woong-Hee
authors: WH
authors: Kim
authors: School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju 61005, Republic of Korea.
authors: Haaglim
authors: H
authors: Cho
authors: School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju 61005, Republic of Korea.
authors: JungIn
authors: J
authors: Um
authors: School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju 61005, Republic of Korea.
authors: Youngha
authors: Y
authors: Seo
authors: Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju, 61469, Republic of Korea.
authors: Wan Seok
authors: WS
authors: Kang
authors: School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju 61005, Republic of Korea.
authors: Suk-Won
authors: SW
authors: Jin
authors: Department of Cardiology, Chonnam National University Hospital, Gwangju 61469, Republic of Korea.
authors: Min Chul
authors: MC
authors: Kim
authors: School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju 61005, Republic of Korea.
authors: Yong-Chul
authors: YC
authors: Kim
authors: School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju 61005, Republic of Korea.
authors: Da-Woon
authors: DW
authors: Jung
authors: School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju 61005, Republic of Korea.
authors: Darren R
authors: DR
authors: Williams
authors: Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju, 61469, Republic of Korea.|Department of Cardiology, Chonnam National University Hospital, Gwangju 61469, Republic of Korea.
authors: Youngkeun
authors: Y
authors: Ahn
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D060833:Cellular Microenvironment / Q000187:drug effects*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010091:Oximes / Q000494:pharmacology*; D051381:Rats; D015027:Zebrafish
chemical_list: D010091:Oximes