title: Statins ameliorate pulmonary hypertension secondary to left ventricular dysfunction through the Rho-kinase pathway and NADPH oxidase.
abstract: 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.
  
  
  
  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 p67Phoxwere 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.
  
  
  
  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, p47Phoxand p67Phox, and upregulated pulmonary p-eNOS, NOx, and cGMP in both the early- and late-treated groups.
  
  
  
  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.
authors.affiliation: Department of Pediatrics, Kaohsiung Medical University Hospital, 100 Shih-Chuan 1st Road, Sun-Ming District, Kaohsiung, Taiwan.|Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: I-Chen
authors.initials: IC
authors.lastname: Chen
authors.affiliation: Department of Biomedical Science and Environmental Biology, College of Life Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Mian-Shin
authors.initials: MS
authors.lastname: Tan
authors.affiliation: Department of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Bin-Nan
authors.initials: BN
authors.lastname: Wu
authors.affiliation: Department of Pathology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chee-Yin
authors.initials: CY
authors.lastname: Chai
authors.affiliation: Department of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jwu-Lai
authors.initials: JL
authors.lastname: Yeh
authors.affiliation: Department of Thoracic Surgery, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shah-Hwa
authors.initials: SH
authors.lastname: Chou
authors.affiliation: Department of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ing-Jun
authors.initials: IJ
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Kaohsiung Medical University Hospital, 100 Shih-Chuan 1st Road, Sun-Ming District, Kaohsiung, Taiwan.|Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Zen-Kong
authors.initials: ZK
authors.lastname: Dai
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D019821:Simvastatin / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017382:Reactive Oxygen Species; D019821:Simvastatin; D019255:NADPH Oxidases; D054460:rho-Associated Kinases
keywords: NADPH oxidase; endothelial nitric oxide synthase; endothelin-1; left ventricular dysfunction; pulmonary hypertension; statin