Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart

Abstract

BACKGROUND: Organ fibrosis due to excessive production of extracellular matrix by resident fibroblasts is estimated to contribute to >45% of deaths in the Western world, including those due to cardiovascular diseases such as heart failure. Here, we screened for small molecule inhibitors with a common ability to suppress activation of fibroblasts across organ systems. METHODS: High-content imaging of cultured cardiac, pulmonary, and renal fibroblasts was used to identify nontoxic compounds that blocked induction of markers of activation in response to the profibrotic stimulus, transforming growth factor-β1. SW033291, which inhibits the eicosanoid-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase, was chosen for follow-up studies with cultured adult rat ventricular fibroblasts and human cardiac fibroblasts (CFs), and for evaluation in mouse models of cardiac fibrosis and diastolic dysfunction. Additional mechanistic studies were performed with CFs treated with exogenous eicosanoids. RESULTS: Nine compounds, including SW033291, shared a common ability to suppress transforming growth factor-β1–mediated activation of cardiac, pulmonary, and renal fibroblasts. SW033291 dose-dependently inhibited transforming growth factor-β1–induced expression of activation markers (eg, α-smooth muscle actin and periostin) in adult rat ventricular fibroblasts and normal human CFs, and reduced contractile capacity of the cells. Remarkably, the 15-hydroxyprostaglandin dehydrogenase inhibitor also reversed constitutive activation of fibroblasts obtained from explanted hearts from patients with heart failure. SW033291 blocked cardiac fibrosis induced by angiotensin II infusion and ameliorated diastolic dysfunction in an alternative model of systemic hypertension driven by combined uninephrectomy and deoxycorticosterone acetate administration. Mechanistically, SW033291-mediated stimulation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signaling was required for SW033291 to block CF activation. Of the 12 exogenous eicosanoids that were tested, only 12-hydroxyeicosatetraenoic acid, which signals through the G protein-coupled receptor, GPR31, recapitulated the suppressive effects of SW033291 on CF activation. CONCLUSIONS: Inhibition of degradation of eicosanoids, arachidonic acid-derived fatty acids that signal through G protein-coupled receptors, is a potential therapeutic strategy for suppression of pathological organ fibrosis. In the heart, we propose that 15-hydroxyprostaglandin dehydrogenase inhibition triggers CF-derived autocrine/paracrine signaling by eicosanoids, including 12-hydroxyeicosatetraenoic acid, to stimulate extracellular signal-regulated kinase 1/2 and block conversion of fibroblasts into activated cells that secrete excessive amounts of extracellular matrix and contribute of heart failure pathogenesis.

The Link between Prostanoids and Cardiovascular Diseases

“…15-PGDH activity promotes cardiac fibrosis, even in the infarcted heart, owing to PGE2 degradation; it has been shown that its deletion promotes cardiac recovery and reduces the fibrosis of the heart, too. This is due to the increased collagen deposition owing to TGF-β1 factor activation, which, in contrast, is inhibited by the PGE2/EP4 axis [ 227 ]. It has been noted that 15-PGDH is overexpressed after coronary artery stent implantation in patients affected by vessel stenosis, lowering the inflammation [ 228 ].…”

RNA sequencing provides novel insights into the pathogenesis of naturally occurring myxomatous mitral valve disease stage B1 in beagle dogs

“…HPGD encodes 15-PGDH, an enzyme that regulates prostaglandin E2 (PGE2) metabolism and is crucial for inflammation control. 15-PGDH malfunction promotes cardiac fibrosis in infarcted hearts by degrading PGE2, leading to increased collagen levels due to transforming growth factor beta 1 activation [ 47 ]. PTGER3 encodes EP3, the PGE2 receptor, and was identified as a candidate gene for blood pressure regulation in human studies [ 48 ].…”

Cell-Based Phenotypic Screen for Antifibrotic Compounds Targets Eicosanoid Metabolism

“…Taken together, Rubino et al 7 demonstrate the power of cell-based phenotypic screens to identify antifibrotic compounds and probe the mechanistic basis of fibroblast plasticity (See Figure). This study began with a hit that targets 15-PGDH, an eicosanoid-degrading enzyme.…”

“…In this issue, Rubino et al 7 report the results of a small molecule screen for antifibrotic compounds. One important aspect of their approach is the development of a cell-based phenotypic screen, complementing recent phenotypic screens using a reporter assay for fibroblast activation.…”