Hypertrophic cardiomyocytes promote cardiac fibrosis through paracrine secretion of ketoisoleucine in pressure-overloaded hearts

Abstract

Cardiac fibrosis is a critical pathological feature that drives pressure overload (PO)-induced heart failure (HF). This process involves a complex intercellular crosstalk between cardiac fibroblasts (CFs) and cardiomyocytes. Cardiomyocyte hypertrophy is a compensatory response to PO and undergoes metabolic reprogramming; however, the specific metabolite(s) transmitting the pro-fibrotic signals from hypertrophic cardiomyocytes to CFs remain largely unknown. In this study, we demonstrated that hypertrophic cardiomyocytes secreted elevated level of isoleucine metabolite ketoisoleucine (Ket), which activated CFs to exacerbate PO-induced cardiac fibrosis and dysfunction. Mechanistically, Ket docked with the membrane transporter MCT1, subsequently activating Smad2/3 signaling to upregulate EGR3 expression and its nuclear accumulation, where EGR3 directly bound to the promoter regions of Acta2 and Col3a1 , driving their transcription and promoting CF activation. Remarkably, inhibition of Ket secretion from hypertrophic cardiomyocytes attenuated their pro-fibrotic effects on CF activation, establishing this pathway as a key driver of PO-induced cardiac remodeling. We identify Ket as a metabolic mediator linking cardiomyocyte hypertrophy to cardiac fibrosis in PO conditions. Targeting the Ket-dependent cardiomyocyte-to-fibroblast signaling axis offers potential therapeutic targets for managing PO-induced HF by limiting pathological cardiac fibrosis.