Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

Abstract

An accumulating body of evidence incriminates Rho kinase (ROCK) in the pathogenesis of pulmonary hypertension (PH). The therapeutic efficacy of azaindole-1, a novel highly selective and orally active ROCK inhibitor, has not yet been investigated in PH.This study aimed to investigate the effects of azaindole-1 on 1) acute hypoxic pulmonary vasoconstriction (HPV), 2) proliferation of pulmonary arterial smooth muscle cells (PASMCs) and 3) animal models of PH.Azaindole-1 significantly inhibited HPV in isolated, ventilated and buffer-perfused murine lungs and proliferation of primary rat PASMCs in vitro. Azaindole-1 was administered orally from 21 to 35 days after monocrotaline (MCT) injection in rats and hypoxic exposure in mice. Azaindole-1 (10 and 30 mg per kg body weight per day in rats and mice, respectively) significantly improved haemodynamics and right ventricular hypertrophy. Moreover, the medial wall thickness and muscularisation of peripheral pulmonary arteries were ameliorated. Azaindole-1 treatment resulted in a decreased immunoreactivity for phospho-myosin phosphatase target subunit 1 and proliferating cell nuclear antigen in pulmonary vessels of MCT-injected rats, suggesting an impaired ROCK activity and reduced proliferating cells.Azaindole-1 provided therapeutic benefit in experimental PH, and this may be attributable to its potent vasorelaxant and antiproliferative effects. Azaindole-1 may offer a useful approach for treatment of PH.KEYWORDS: Azaindole-1, hypoxia, monocrotaline, pulmonary hypertension, Rho kinase P ulmonary arterial hypertension (PAH) is a chronic fatal disease characterised by sustained elevation of pulmonary artery pressure and reduced exercise tolerance. As a consequence, the right ventricular afterload increases and culminates in right ventricular failure. PAH has a complex pulmonary vascular pathophysiology, including vasoconstriction, vascular remodelling and in situ thrombosis. The progressive vascular remodelling, the hallmark of PAH pathology, is attributable to abnormalities in vascular cells, such as increased proliferation and resistance to apoptosis [1][2][3]. However, the precise molecular mechanism is incompletely understood, and so a therapeutic approach for curing this disease is currently sought after.The small GTPase RhoA is one of the members of the Rho protein family that regulate cellular functions such as contraction, motility, proliferation and apoptosis, and Rho kinases (ROCKs) are the best characterised downstream targets for RhoA [4]. Two isoforms of the serine/threonine kinase ROCK have been identified: . ROCKs are ubiquitously expressed in tissues including vasculature and heart. Owing to its role in key cell functions, hyperactive ROCK signalling results in cardiovascular disorders associated with sustained abnormal vasoconstriction and promotion of vascular remodelling [8,9]. Studies on animal models of pulmonary hypertension (PH), such as chronic hypoxia-, monocrotaline (MCT)-, vascular endothelial growth factor receptor inhibition and chron...

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“…Bleomycin-instilled hamsters were randomised into two groups and treated orally by gavage either with chymase inhibitor BCEAB (4-[1-([bis-(4-methyl-phenyl)-methyl]-carbamoyl) 3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid) (Bleo-BCEAB) or placebo (Bleo-placebo). Haemodynamic and right heart hypertrophy (RHH) measurements were performed similarly as previously described [32].…”

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