Sertad4 regulates pathological cardiac remodeling.

Abstract

Cardiac fibrosis driven by persistent myofibroblast activation is a major contributor to adverse ventricular remodeling and heart failure. Bromodomain and extra-terminal domain (BET) inhibition reduces fibrosis and hypertrophy in preclinical models, but direct targeting of the BET co-activator BRD4 is limited by family homology and potential systemic toxicity. Sertad4 (SERTA domain containing protein 4) is a BRD4-dependent gene induced in activated cardiac fibroblasts, yet its role in cardiac pathology is unknown. Here, we examined Sertad4 expression and function in human heart failure and in murine myocardial infarction (MI). SERTAD4 protein was increased in left ventricular tissue from heart failure patients compared with non-failing controls. In Sertad4/LacZ reporter mice, MI triggered strong Sertad4 activation localized to the infarct scar and border zone, with minimal expression in remote myocardium; single-nucleus RNA sequencing further demonstrated that Sertad4 expression is predominantly fibroblast-restricted and significantly upregulated after MI. To test causality, we subjected global Sertad4 knockout mice to 28-day left anterior descending coronary artery ligation. Sertad4 deletion attenuated post-MI remodeling, reduced hypertrophy and ventricular dilation, and preserved systolic function. Consistent with improved structure and function, knockout hearts exhibited reduced cardiomyocyte cross-sectional area and decreased expression of fibrosis and hypertrophy associated genes. Together, these findings identify Sertad4 as a fibroblast enriched regulator of pathological remodeling and suggest that targeting Sertad4 may offer a more cell type-selective alternative to direct BET/BRD4 inhibition for limiting cardiac fibrosis and progression to heart failure