Gerozyme Inhibition as an Antifibrotic Therapeutic Strategy for Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a progressive cardiac disorder marked by ventricular dilation, reduced contractile function, and pathological fibrosis, often culminating in heart failure. While current therapies focus on symptom management, they do not directly target the fibrotic remodeling that underpins disease progression. This study identifies 15-hydroxyprostaglandin dehydrogenase (15-PGDH, or "gerozyme," an enzyme that accumulates with aging) as a key mediator of cardiac fibrosis and proposes its inhibition as a therapeutic strategy for DCM. Using the TM54 transgenic mouse model of DCM, we found that gerozyme expression was elevated, correlating with a reduction in prostaglandin E2 (PGE2), a lipid mediator with known antifibrotic properties. Inhibiting the gerozyme with the small molecule SW033291 (SW) restored PGE2 levels, significantly improved cardiac function, and reduced myocardial fibrosis. Histological analysis confirmed decreased collagen deposition, and transcriptomic profiling revealed suppression of fibrosis-related gene expression and TGF-β signaling pathways. In vitro, PGE2 prevented the transdifferentiation of human cardiac fibroblasts into profibrotic myofibroblasts. Mechanistically, these effects were mediated through PGE2’s inhibition of serum response factor (SRF), a transcription factor downstream of TGF-β signaling. Additionally, gerozyme inhibition promoted endothelial cell branching and expression of angiogenic genes, suggestive of improved vascular remodeling. Together, these findings position gerozyme inhibition as a promising antifibrotic therapeutic strategy for DCM. By modulating the PGE2-SRF axis, this approach not only attenuates fibrosis but also enhances cardiac function and vascularization, offering a novel therapeutic avenue for fibrotic cardiac disease.