Pediatric Pulmonology Statins Ameliorate Pulmonary Hypertension Secondary to Left Ventricular Dysfunction Through the Rho-Kinase Pathway and NADPH Oxidase I-Chen Chen, MD, 1,2 Mian-Shin Tan, PhD, 3 Bin-Nan Wu, PhD, 4 Chee-Yin Chai, MD, PhD, 5 Jwu-Lai Yeh, PhD, 4 Shah-Hwa Chou, MD, PhD, 6 Ing-Jun Chen, PhD, 4 and Zen-Kong Dai, MD, PhD 1,2 * 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 , p47 Phox , and p67 Phox 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, p47 Phox and p67 Phox , 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. 2016; 9999:XX--XX. ß 2016 Wiley Periodicals, Inc. Key words: pulmonary hypertension; left ventricular dysfunction; statin; NADPH oxidase; endothelial nitric oxide synthase; endothelin-1. Funding source: Ministry of Science and Technology, R.O.C., Number: MOST103-2314-B- 037-023-MY3; Kaohsiung Medical University Hospital, Number: KMUH102-2R26. 1 Department of Pediatrics, Kaohsiung Medical University Hospital, 100 Shih-Chuan 1st Road, Sun-Ming District, Kaohsiung, Taiwan. 2 Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 3 Department of Biomedical Science and Environmental Biology, College of Life Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan. 4 Department of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 5 Department of Pathology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 6 Department of Thoracic Surgery, Kaohsiung Medical University, Kaohsiung, Taiwan. Conflict of interest: None.  Correspondence to: Zen-Kong Dai, MD, PhD, Department of Pediatrics, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Sun-Ming District, Kaohsiung, Taiwan. E-mail: zenkong@kmu.edu.tw Received 9 November 2015; Revised 31 July 2016; Accepted 18 September 2016. DOI 10.1002/ppul.23610 Published online in Wiley Online Library (wileyonlinelibrary.com). ß 2016 Wiley Periodicals, Inc.