EP4 Agonist L-902,688 Suppresses EndMT and Attenuates Right Ventricular Cardiac Fibrosis in Experimental Pulmonary Arterial Hypertension.

Ying-Ju Lai,Chung-Chi Huang,Hsin-Hsien Li,I-Chen Chen

doi:10.3390/ijms19030727

Abstract

Right ventricular (RV) hypertrophy is characterized by cardiac fibrosis due to endothelial–mesenchymal transition (EndMT) and increased collagen production in pulmonary arterial hypertension (PAH) patients, but the mechanisms for restoring RV function are unclear. Prostanoid agonists are effective vasodilators for PAH treatment that bind selective prostanoid receptors to modulate vascular dilation. The importance of prostanoid signaling in the RV is not clear. We investigated the effects of the EP4-specific agonist L-902,688 on cardiac fibrosis and TGF-β-induced EndMT. EP4-specific agonist treatment reduced right ventricle fibrosis in the monocrotaline (MCT)-induced PAH rat model. L-902,688 (1 µM) attenuated TGF-β-induced Twist and α-smooth muscle actin (α-SMA) expression, but these effects were reversed by AH23848 (an EP4 antagonist), highlighting the crucial role of EP4 in suppressing TGF-β-induced EndMT. These data indicate that the selective EP4 agonist L-902,688 attenuates RV fibrosis and suggest a potential approach to reducing RV fibrosis in patients with PAH.

Highlights

Right ventricular (RV) hypertrophy and failure are major causes of morbidity and mortality in patients with pulmonary arterial hypertension (PAH) [1,2]
These data suggest that the inhibitory effect of the EP4 agonist L-902,688 on RV fibrosis might be mediated by suppression of α-smooth muscle actin (α-SMA) and Twist, the endothelial–mesenchymal transition (EndMT) markers
Western blot analysis of endothelial cell marker and mesenchymal and EndMT marker (Twist and α-SMA) on TGF-β1-induced EndMT (Figure 1A) expression showed that α-SMA and Twist expression levels were strongly decreased by treatment with 1 μM L-902,688 Int.(JF. iMguolr. eSc1i.B)2.0T18a,k1e9n, 7t2o7gether, these data suggest that the inhibitory effect of the EP4 agonist L-902,638o8f 12 on RV fibrosis might be mediated by suppression of α-SMA and Twist, the EndMT markers

Summary

Introduction

Right ventricular (RV) hypertrophy and failure are major causes of morbidity and mortality in patients with pulmonary arterial hypertension (PAH) [1,2]. RV hypertrophy is characterized by cardiac fibrosis due to myocardial apoptosis, endothelial dysfunction, and endothelial–mesenchymal transition (EndMT) as well as the accumulation of collagen production [3]. These pathways have been therapeutically targeted with phosphodiesterase type 5 inhibitors (sildenafil), endothelin antagonists, soluble guanylate cyclase (sGC) stimulator (riociguat), and prostanoid agonists [2,4,5]. Prostanoid receptors (IP, EP2, EP4, and DP) couple with stimulatory G protein (Gs) to elevate intracellular cyclic adenosine monophosphate (cAMP) and promote vascular relaxation [9]. EP1, EP3, FP, and TP couple with inhibitory G protein (Gi) to reduce intracellular cAMP or elevate Ca2+ levels [9]

Methods

Results

Conclusion