Inhibition of CDK1 attenuates cardiac remodeling via suppression of fibroblast-derived TGF-β1

Activation of cyclin-dependent kinase 1 (CDK1) is implicated in fibrosis in liver and skin. However, the role of CDK1 in cardiac remodeling remains unclear. We investigated whether CDK1 inhibition suppresses cardiac remodeling and explored the underlying mechanisms. Angiotensin II (Ang II) was continuously infused into C57BL/6 mice with or without intraperitoneal administration of a selective CDK1 inhibitor (Ro-3306) for 1 week. Ro-3306 attenuated Ang II-induced increases in left ventricular wall thickness and heart weight without affecting blood pressure. Ro-3306 also ameliorated interstitial fibrosis and cardiomyocyte hypertrophy in Ang II-treated hearts, accompanied by reduced Col1a1 and Col3a1 mRNA expression. Ang II increased phosphorylation of CDK1 substrate motifs and transforming growth factor-β1 (TGF-β1) precursor protein levels, a key mediator of cardiac fibrosis and hypertrophy, and these were suppressed by Ro-3306. Ro-3306 also attenuated pressure overload-induced cardiac fibrosis and hypertrophy, accompanied by reduced TGF-β1 precursor protein levels. In cultured cardiac fibroblasts, inhibition of CDK1 by Ro-3306 or small interfering RNA suppressed Ang II-induced increases in TGF-β1 precursor protein levels, whereas no such effect was observed in cultured cardiomyocytes. In contrast, CDK2 knockdown or CDK4/6 inhibitors did not affect TGF-β1 precursor protein levels in cardiac fibroblasts. Comprehensive secretome analysis identified TGF-β1 as a major growth factor secreted from fibroblasts in response to Ang II. Conditioned medium from fibroblasts treated with Ang II induced cardiomyocyte hypertrophy. CDK1 knockdown in fibroblasts suppressed TGF-β1 secretion. Neutralizing TGF-β1 antibodies attenuated hypertrophic effects of conditioned medium from fibroblasts treated with Ang II. In conclusion, CDK1 inhibition attenuates cardiac fibrosis and hypertrophy in vivo, accompanied by reduced cardiac TGF-β1 precursor protein levels. Our in vitro findings further suggest that CDK1 in cardiac fibroblasts regulates TGF-β1 production and secretion, thereby contributing to cardiomyocyte hypertrophy.