Periostin Mediates Right Ventricular Failure through Induction of Inducible Nitric Oxide Synthase Expression in Right Ventricular Fibroblasts from Monocrotaline-Induced Pulmonary Arterial Hypertensive Rats.

Keisuke Imoto,Hideyuki Yamawaki,Muneyoshi Okada

doi:10.3390/ijms20010062

Keisuke Imoto, Hideyuki Yamawaki + Show 1 more

Open Access

https://doi.org/10.3390/ijms20010062

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Abstract

Pulmonary arterial hypertension (PAH) leads to lethal right ventricular failure (RVF). Periostin (POSTN) mRNA expression is increased in right ventricles (RVs) of monocrotaline (MCT)-induced PAH model rats. However, the pathophysiological role of POSTN in RVF has not been clarified. We investigated the effects of POSTN on inducible nitric oxide (NO) synthase (iNOS) expression and NO production, which causes cardiac dysfunction, in right ventricular fibroblasts (RVFbs). Male Wistar rats were intraperitoneally injected with MCT (60 mg/kg) or saline. Three weeks after injection, RVFbs were isolated from RVs of MCT- or saline-injected rats (MCT-RVFb or CONT-RVFb). In MCT-RVFb, iNOS expression and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) were higher than those in CONT-RVFb. Recombinant POSTN increased iNOS expression and NO production, which were prevented by a pharmacological inhibition of ERK1/2, JNK or NF-κB in RVFbs isolated from normal rats. Culture medium of POSTN-stimulated RVFbs suppressed Ca2+ inflow through l-type Ca2+ channel (LTCC) in H9c2 cardiomyoblasts. We demonstrated that POSTN enhances iNOS expression and subsequent NO production via ERK1/2, JNK, and NF-κB signaling pathways in RVFbs. POSTN might mediate RVF through the suppression of LTCC activity of cardiomyocytes by producing NO from RVFbs in PAH model rats.

Highlights

Pulmonary arterial hypertension (PAH) is characterized by a constriction of pulmonary artery by progressive vascular remodeling, which elevates pulmonary arterial resistance
Expression of POSTN Was Increased in right ventricles (RVs) of MCT-Injected Rats 2.1
We showed that the protein expression of POSTN in RVs was increased in MCT (3 weeks)-injected but not MCT (2 weeks)-injected rats (Figure 1a)

Summary

Introduction

Pulmonary arterial hypertension (PAH) is characterized by a constriction of pulmonary artery by progressive vascular remodeling, which elevates pulmonary arterial resistance. For the management of PAH, pulmonary arterial vasodilators, such as endothelin receptor antagonist, phosphodiesterase-5 inhibitors and prostacyclin analogs, are widely used in recent two decades [1,2]. The vasodilators have effectively reduced mortality of PAH patients, it still remains high throughout the world [3,4,5]. PAH leads to right ventricular (RV) hypertrophy and subsequent lethal RV failure (RVF). A novel therapeutic strategy for PAH-induced RVF has been awaited. RV systolic dysfunction caused by RV diastolic stiffness worsens along with deterioration of RVF [6,7]. The mechanisms underlying initiation and progression of PAH-induced RVF have not been fully clarified

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