Statins ameliorate pulmonary hypertension secondary to left ventricular dysfunction through the Rho‐kinase pathway and NADPH oxidase

• Published in: Pediatric pulmonology 2017-04, Vol.52 (4), p.443-457
• Main Authors: Chen, I‐Chen, Tan, Mian‐Shin, Wu, Bin‐Nan, Chai, Chee‐Yin, Yeh, Jwu‐Lai, Chou, Shah‐Hwa, Chen, Ing‐Jun, Dai, Zen‐Kong
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; endothelial nitric oxide synthase; endothelin‐1; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Hypertension, Pulmonary - complications; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - metabolism; left ventricular dysfunction; Male; NADPH oxidase; NADPH Oxidases - metabolism; Nitric oxide; Pulmonary arteries; Pulmonary hypertension; Rats; Rats, Wistar; Reactive oxygen species; Reactive Oxygen Species - metabolism; rho-Associated Kinases - metabolism; Simvastatin - therapeutic use; statin; Statins; Ventricular Dysfunction, Left - complications; Ventricular Dysfunction, Left - drug therapy; Ventricular Dysfunction, Left - metabolism
• ISSN: 8755-6863; 1099-0496
• DOI: 10.1002/ppul.23610

Summary Background Pulmonary hypertension (PH) is a devastating disorder, for which no therapy is curative. It has been reported that pulmonary vascular remodeling, associated with increasing mean pulmonary arterial pressure and upregulated expression of endothelial nitric oxide synthase (eNOS), endothelin‐1 (ET‐1), RhoA/RhoH‐kinase results in the development of PH. Oxidative stress and the RhoA/Rho‐kinase pathway are also thought to be involved in the pathophysiology of PH. Statins are 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (HMG‐CoA reductase inhibitors) with pleiotropic effects and are potential agents for the treatment of PH. In this study, we investigated the beneficial effects of simvastatin on the development of PH secondary to left ventricular dysfunction. Methods A PH secondary to left ventricular dysfunction model was established in 6‐week‐old aortic‐banded rats. The pulmonary expression of Rho kinase, ET‐1, eNOS, p‐eNOS, nitrite/nitrate (NOx), cGMP, p47Phox, and p67Phox were investigated in the early‐treatment group, to which was administered simvastatin (30 mg/kg/day) from days 1 to 42 or the late‐treatment group, to which was administered simvastatin (30 mg/kg/day) from days 29 to 42. Results Simvastatin attenuated the mean pulmonary artery pressure, pulmonary arteriolar remodeling, plasma brain natriuretic peptide, ET‐1, reactive oxygen species, and the NADPH oxidase 2 regulatory subunits, p47Phox and p67Phox, and upregulated pulmonary p‐eNOS, NOx, and cGMP in both the early‐ and late‐treated groups. Conclusions Inhibiting HMG‐CoA reductase may have therapeutic potential for preventing and attenuating the development of PH in left ventricular dysfunction through the Rho‐kinase pathway and NADPH oxidase. A translational study in humans is needed to substantiate these findings. Pediatr Pulmonol. 2017;52:443–457. © 2016 Wiley Periodicals, Inc.