Abstract 4361118: Fibroblast-Derived CLEC11A Drives Pathological Cardiac Hypertrophy and Fibrosis

Background: Cardiac hypertrophy can be either physiological or pathological. Physiological hypertrophy, typically induced by exercise, is adaptive and associated with minimal fibrosis. In contrast, pathological hypertrophy often progresses to heart failure (HF) and is characterized by interstitial and perivascular fibrosis. We sought to identify fibroblast (FB)-specific pathways that drive these divergent outcomes. Methods: Primary cardiac FBs were isolated from mouse hearts with physiological hypertrophy (8-week voluntary wheel running), pathological hypertrophy (transverse aortic constriction, TAC-2w), or HF (TAC-8w), along with their controls, for RNA-seq. Differentially expressed genes (DEGs) were identified and compared to known FB/myofibroblast markers from single-cell RNA-seq datasets of human dilated (DCM) and hypertrophic cardiomyopathy (HCM). CLEC11A emerged as a top candidate and was further evaluated using spatial transcriptomics of human HCM hearts, data from the UK Biobank, and functional assays in vitro and in vivo. Bulk RNA-seq was performed on CLEC11A-overexpressing hearts to assess downstream signaling. Results: CLEC11A, a secreted protein, was upregulated in TAC-induced hypertrophy (1.89-fold) and HF (1.85-fold) but downregulated in exercised hearts (−0.99-fold). It was highly expressed in FBs and myofibroblasts. In HCM hearts, spatial transcriptomics confirmed increased CLEC11A expression, co-localizing with POSTN, a known FB marker. Elevated circulating CLEC11A in the UK Biobank cohort (N=50,851) was strongly associated with prevalent HF (odd ratio=2.0, p =1.68×10 -15 ). In vivo overexpression of CLEC11A in FBs via AAV9-TCF21-CLEC11A led to pathological hypertrophy (LVM 81.4 vs 102.7 mg, p<0.001) and reduced cardiac function (EF 58.7% vs 42.1%, p<0.001). RNA-seq revealed enrichment of pro-hypertrophic pathways, notably JAK-STAT (NES=1.54, p<0.01). Single-cell analysis showed that dysregulated targets of CLEC11A were mainly expressed in FBs and cardiomyocytes. In vitro, recombinant CLEC11A increased Acta2 and Col3a1 in FBs and induced hypertrophy in neonatal cardiomyocytes. Conclusion: CLEC11A is a fibroblast-derived secreted factor that promotes FB activation, pathological hypertrophy, and HF. These findings highlight an upstream role for FBs in adverse cardiac remodeling and suggest CLEC11A as a potential therapeutic target in fibrosis and HF.