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.
Highlights
Medical interventions have been developed to stabilize patients with myocardial infarction (MI), which has improved survival rates, but there is currently no clinically approved method to reverse the loss of cardiac muscle
BIO treatment significantly decreased proliferation in cardiac fibroblasts. n = 5, *p < 0.05, t-test. (D) The increase in cardiomyocyte proliferation after treatment with BIO for 4 days was confirmed by MTT assay. (E) The numbers of proliferating cardiomyocytes and cardiac fibroblasts were determined by immunofluorescence staining with BrdU, and 5 μM BIO treatment of cardiomyocyte: cardiac fibroblast co-cultures for 2 days did not affect the proportions of proliferating and non-proliferating cells. n = 4, *p < 0.05, t-test. (F) The numbers of proliferating cardiomyocytes and cardiac fibroblasts were determined by immunofluorescence staining with BrdU, and 5 μM BIO treatment of co-cultures for 5 days produced a significant increase in the proportion of proliferating cardiomyocytes compared to non-proliferating cardiomyocytes
Our results show that BIO induces proliferation in cardiomyocytes and inhibits proliferation in cardiac fibroblasts (Fig. 1)
Summary
Medical interventions have been developed to stabilize patients with MI, which has improved survival rates, but there is currently no clinically approved method to reverse the loss of cardiac muscle (cardiomyocytes).
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