Abstract 9339: Cardiac Fibroblasts Are Critically Involved in the Development of Heart Failure by Inducing Cardiomyocyte Senescence

Abstract

Introduction: Tissue fibrosis and cellular senescence are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Besides, the clinical significance of the cellular senescence seen in heart failure also remains unclear. Methods and Results: Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we focused and elucidated the role of high-temperature requirement A serine peptidase 3 (Htra3) which is expressed specifically in cardiac fibroblast. We found that Htra3 governs the identity of quiescent cardiac fibroblasts through degradation of TGF-β. Expression of Htra3 was downregulated by pressure overload in cardiac fibroblasts. Htra3 deletion in the murine heart caused overactivation of TGF-β signalling which induced not only significant cardiac fibrosis, but also cardiomyocyte senescence through DNA damage accumulation by repressing DNA repair factors and activating NADPH oxidase Nox4. Overexpression of Htra3 in the murine heart inhibited TGF-β signalling and ameliorated cardiac dysfunction as well as fibrosis after pressure overload. Htra3-regulated spatio-temporal cardiac fibrosis and cardiomyocyte senescence were also observed specifically in infarct regions after myocardial infarction. Furthermore, the senescent transcriptional profile observed in Htra3 knock-out murine cardiomyocytes were also seen in the cardiomyocytes from end-stage heart failure patients. Integrative analyses of human single-cardiomyocyte transcriptome and plasma proteome revealed that IGFBP7, which is a cytokine downstream of TGF-β and secreted from senescent cardiomyocytes, was the most predictable marker of advanced heart failure. Conclusions: Htra3 is a critical regulator of cardiac fibrosis and also affects cardiomyocyte senescence through the intercellular signalling communication between cardiac fibroblasts and cardiomyocytes. Our findings highlight the previously unknown roles of cardiac fibroblasts in regulating cardiomyocyte senescence as well as cardiac fibrosis through the Htra3-TGF-β-IGFBP7 pathway, which would be a novel therapeutic target for heart failure.