Pulmonary hypertension (PH) is a severe chronic and life-threatening disease characterized by progressive augmentation of pulmonary arterial pressure that finally leads to right ventricle failure and death. PH has a multi-complex pathology which includes a combination of pulmonary vascular remodelling, vasoconstriction and in situ thrombosis. Key to the severity of the disease is the progressive pulmonary vascular remodelling. The progressive pulmonary vascular remodelling is the attribute of PH pathology and is characterized by abnormalities of vascular cells such as increased proliferation, migration and resistance to apoptosis. Although the PH pathology is the subject of intensive research the precise molecular mechanisms are still not fully understood and successful therapeutic strategy to cure the disease is still needed.An accumulating body of evidence incriminates Rho-kinase (ROCK) in the pathogenesis of PH and suggests the Rho-kinase as a promising therapeutic target. In the line with literature, our study aimed to investigate the therapeutic effects of a novel highly selective and orally active ROCK inhibitor, azaindole-1 in animal models of PH. We successfully demonstrated that azaindole-1 significantly inhibited hypoxic pulmonary vasoconstriction in isolated, ventilated and buffer-perfused murine lungs and proliferation of primary rat pulmonary artery smooth muscle cells in vitro. Furthermore, azaindole-1 chronic treatment improved hemodynamics and right ventricular hypertrophy in both experimental models of PH. Moreover, the medial wall thickness and muscularization of peripheral pulmonary arteries, as measures of pulmonary vascular remodelling, were significantly ameliorated. Finally, azaindole-1 treatment resulted in a decreased immunoreactivity for phospho-myosin phosphatase target subunit-1 (p-MYPT-1) and proliferating cell nuclear antigen (PCNA) in pulmonary vessels of monocrotaline-injected rats, suggesting an impaired ROCK activity and reduced proliferating vascular cells.In conclusion, azaindole-1 provided therapeutic benefit in experimental PH and this may be attributable to its potent vasorelaxant and antiproliferative effects. Thus, azaindole-1 may offer a useful approach for the treatment of pulmonary hypertension and may have a potential clinical application.
Verknüpfung zu Publikationen oder weiteren Datensätzen
