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.

Interventions in WNT Signaling to Induce Cardiomyocyte Proliferation: Crosstalk with Other Pathways

“…Administration of tamoxifen from 3 to 8 days post-MI did not reduce infarct size but improved cardiac function at 8 weeks post-MI and more than doubled the BrdU incorporation in CMs in the border zone (Woulfe et al, 2010). Administration of the GSK3-b-inhibitor BIO to infarcted rats for 2 weeks resulted in reduced ventricular fibrosis and improved cardiac function, but changes in infarct size or stimulation of CM proliferation were not reported in this study (Kim et al, 2016). Recently, Badimon et al (2019) reported a small but significant decrease in infarct size in mice treated with the GSK3 inhibitor SB415286; however, this effect was only observed in an ischemia-reperfusion model and not after permanent coronary ligation (Badimon et al, 2019).…”

“…Activation of WNT signaling via GSK3-b inhibition with BIO (5 mM) resulted in a 10-fold increase in BrdU incorporation and a 5-fold increase in phosphorylated histone-3-positive cells (Tseng et al, 2006). These results were confirmed by Kim et al (2016), who showed that BIO not only induced BrdU incorporation in cultured neonatal rat CMs but also reduced BrdU incorporation in rat neonatal cardiac fibroblasts. Increased proliferation was also observed in cultured human atrial CMs treated with the GSK3-b inhibitor CHIR99021, albeit that the increase in proliferating CMs was modest (control: 1.83% 6 0.01%; CHIR: 2.67% 6 0.08%); in this study, inhibition of WNT/b-catenin signaling with 4-(1,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-methano-2H-isoindol-2-yl)-N-8-quinolinyl-benzamide (IWR-1) resulted in a ∼35% reduction in CM proliferation (Wang et al, 2016).…”

Antiinflammatory activity of ANGPTL4 facilitates macrophage polarization to induce cardiac repair

“…When this normal process is not controlled, chronic inflammation leads to functional decline without sufficient repair. A delicate regulation of macrophage phenotype is thus functionally relevant to tissue repair, and we previously showed that chemical-induced macrophage modulation can significantly contribute to cardiac recovery after myocardial infarction (MI) (8)(9)(10).…”

The Role of Metabolic Remodeling in Macrophage Polarization and Its Effect on Skeletal Muscle Regeneration

“…The MF-reprogramming approach against cachexia of cardiac origin is supported by preclinical studies demonstrating that M2 polarization (e.g., by EPA) is beneficial for the myocardium, by reducing inflammation and promoting cardiac healing after myocardial infarction (52,111,160,326,341). M2 polarization also counteracts systemic and plaque inflammation in atherosclerotic disorders, thus reducing CHF-associated factors (119,299).…”