Suppressor of variegation 3–9 homolog 1 deficiency attenuates cardiac fibrosis and rescues heart failure through TACC2

AIMS: Aberrant and excessive cardiac fibrosis contributes to heart failure. Resident cardiac fibroblasts are the primary source of myofibroblasts that produce extracellular matrix proteins to mediate cardiac fibrosis. Previous studies have implicated suppressor of variegation 3-9 homolog 1 (Suv39h1), a lysine methyltransferase, in liver fibrosis. In the present study, we investigated the involvement of Suv39h1 in cardiac fibrosis. METHODS AND RESULTS: Suv39h1 expression was up-regulated in cardiac fibroblasts in response to a panel of different pro-fibrogenic stimuli including transforming growth factor (TGF-β), angiotensin II (Ang II), and endothelin (ET-1). Suv39h1 ablation attenuated fibroblast-myofibroblast transition (FMyT) as evidenced by expression of myofibroblast markers, cell proliferation, migration, and contraction. Consistently, ablation of Suv39h1 from quiescent fibroblasts (driven by the Col1a2-CreERT) or activated fibroblasts (driven by the PostnMCM) ameliorated cardiac fibrosis and rescued heart function in an animal model of heart failure induced by transverse aortic constriction (TAC). RNA-seq and CUT&Tag-seq uncovered transforming acidic coiled-coil containing protein 2 (TACC2) as a novel target of Suv39h1. Suv39h1 directly bound to the Tacc2 promoter and repressed Tacc2 transcription by catalyzing H3K9 trimethylation during FMyT. Congruently, TACC2 depletion normalized FMyT despite Suv39h1 deficiency whereas TACC2 over-expression suppressed FMyT. Importantly, a small-molecule Suv39h1 inhibitor (F5446) was shown to display antifibrotic effects both in cell culture and in mice. CONCLUSION: Our data suggest that Suv39h1 may play a role in cardiac fibrosis. Targeting Suv39h1 can be considered as a reasonable approach for the intervention of heart failure.