15-PGDH-Mediated Eicosanoid Degradation in Cardiac Fibrosis and Heart Failure

Project Summary/Abstract Fibrosis is defined as excess deposition of extracellular matrix (ECM), resulting in tissue scarring and organ dysfunction. In the heart, fibrotic remodeling in the context of chronic comorbidities such as hypertension and metabolic disease is associated with increased passive myocardial stiffness and the development of diastolic

dysfunction (DD), a contributor to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). The adult heart contains resident cardiac fibroblasts (CFs), which, in response to stress, undergo a cell state transition to become activated fibroblasts, sometimes referred to as myofibroblasts. Activated CFs are characterized by

transcriptional reprogramming that results in enhanced production and secretion of fibrotic ECM proteins. Despite the well-recognized roles of CFs in fibrotic remodeling of the heart, there are no targeted therapies to prevent or reverse the phenotypic conversion of these cells into an activated state.

Recently, we demonstrated that inhibition of the eicosanoid-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using SW033291, potently suppresses murine and human CF activation, and blocks cardiac fibrosis and ameliorates DD in vivo in mice. Eicosanoids are 20 carbon-containing lipid signaling

molecules that are produced by a variety of cells. Our data support a model in which stress signals trigger 15- PGDH-mediated degradation of eicosanoids in CFs, resulting in reduced ERK1/2 signaling and subsequent activation of the cells to promote fibrosis. SW033291 treatment prevents degradation of eicosanoids, resulting

in increased secretion of these fatty acids, which function in an autocrine and paracrine manner to promote antifibrotic ERK signaling in CFs and ameliorate fibrosis of the heart. Three specific aims are designed to extend this new field of cardiac research and test the overall hypothesis that inhibition of 15-PGDH promotes signaling

events that prevent and reverse the transcriptional reprogramming that typically culminates in CF activation and pathological fibrosis of the heart.