CDK Inhibitor R547 Attenuates Pressure Overload-Induced Cardiac Hypertrophy via PI3K/AKT and TGF-β/Smad3 Signaling Pathways.

Abstract

Chronic stress-induced cardiac hypertrophy remains a critical precursor to heart failure, with current therapies limited by incomplete mechanistic targeting. Cyclin-dependent kinases (CDKs), pivotal regulators of cell cycle and stress signaling, are emerging therapeutic targets in cardiovascular pathologies. Using bioinformatics analysis of human hypertrophic cardiomyopathy datasets (GSE5500, GSE136308) and a murine transverse aortic constriction (TAC) model, we investigated the therapeutic effects of the CDK inhibitor R547 (10 mg/kg, intraperitoneal every 3 days) on pressure overload-induced cardiac remodeling. Cardiac function was assessed by echocardiography, while molecular mechanisms were probed through proteomics and pathway analyses. CDKs was significantly upregulated in heart tissues of human heart failure and TAC mice. R547 treatment attenuated cardiac hypertrophy (↓37.7% cardiomyocyte cross-sectional area; P<0.001) and fibrosis (↓70.8% collagen volume fraction; P<0.05) versus TAC controls. Echocardiographic improvements included preserved left ventricular ejection fraction (66±2.1% vs. 81±4.9% in TAC; P<0.05) and reduced ventricular wall thickening. Mechanistically, R547 concurrently inhibited PI3K/AKT/mTOR hypertrophic signaling and TGF-β/Smad3 fibrotic pathways, with corresponding downregulation of ANP, BNP, β-MHC, and collagen I. This study identifies CDK-driven signaling as a nodal regulator of pressure overload cardiomyopathy. The dual inhibition of PI3K/AKT and TGF-β/Smad3 pathways by R547 demonstrates superior efficacy in mitigating both structural and functional deterioration, positioning it as a promising multifactorial therapy for cardiac hypertrophy.