title: Administration of antioxidant peptide SS-31 attenuates transverse aortic constriction-induced pulmonary arterial hypertension in mice.
abstract: OBJECTIVE
  Antioxidant peptide SS-31 is a class of cell-permeable small peptides, which selectively resides on the inner mitochondrial membrane and possesses intrinsic mitochondrial protective capacities. In this study we investigated the therapeutic effects of antioxidant peptide SS-31 on transverse aortic constriction (TAC)-induced pulmonary arterial hypertension (PAH) in a murine model.
  
  
  METHODS
  Adult male mice were divided into 3 groups: sham-operated mice, TAC mice, and TAC+SS-31 mice that underwent TAC surgery and received SS-31 (2 mg/d, ip) for 60 d. The right ventricular systolic blood pressure (RVSBP) was measured on d 60 prior to sacrificing the mice; then their right heart and lung tissues were collected for histological and biochemical examinations. Lung injury scores were defined by the increased crowded area and decreased number of alveolar sacs.
  
  
  RESULTS
  TAC mice showed significantly higher RVSBP compared with sham-operated mice, the elevation was substantially suppressed in TAC+SS-31 mice. The same pattern of changes was found in pulmonary levels of oxidative stress proteins (NOX-1/NOX-2/oxidized proteins), cytosolic cytochrome c, biomarkers related to inflammation (MMP-9/TNF-α/iNOS), calcium overload index (TRPC1, 2, 4, 6), apoptosis (mitochondrial BAX, cleaved caspase 3/PARP), fibrosis (Smad3/TGF-β), hypoxic (HIF-1α), DNA damage (γ-H2AX) and endothelial function (eNOS/ET-1R), as well as in lung injury score, number of muscularized vessels in lungs, number of TRPC1(+) and HIF-1α(+) cells in pulmonary artery, and number of γ-H2AX(+) and Ki-67(+) cells in lung parenchyma. An opposite pattern of changes was observed in pulmonary anti-fibrotic markers (Smad1/5, BMP-2), number of small vessels, and number of alveolar sacs. In contrast, the levels of antioxidant proteins (HO-1/NQO-1/GR/GPx) in lung parenchyma were progressively and significantly increased from sham-operated mice, TAC mice to TAC+SS-31 mice.
  
  
  CONCLUSIONS
  Antioxidant peptide SS-31 administration effectively attenuates TAC-induced PAH in mice.
authors.affiliation: Division of Thoracic and Cardiovascular Surgery, Department of Surgery.
authors.forename: Hung-I
authors.initials: HI
authors.lastname: Lu
authors.affiliation: Division of Cardiology, Department of Internal Medicine.
authors.forename: Tien-Hung
authors.initials: TH
authors.lastname: Huang
authors.affiliation: Division of Cardiology, Department of Internal Medicine.
authors.forename: Pei-Hsun
authors.initials: PH
authors.lastname: Sung
authors.affiliation: Division of Cardiology, Department of Internal Medicine.
authors.forename: Yung-Lung
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Department of Internal Medicine.|Institute for Translational Research in Biomedicine.
authors.forename: Sarah
authors.initials: S
authors.lastname: Chua
authors.affiliation: Division of Cardiology, Department of Internal Medicine.
authors.forename: Han-Yan
authors.initials: HY
authors.lastname: Chai
authors.affiliation: Division of Cardiology, Department of Internal Medicine.
authors.forename: Sheng-Ying
authors.initials: SY
authors.lastname: Chung
authors.affiliation: Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, China.
authors.forename: Chu-Feng
authors.initials: CF
authors.lastname: Liu
authors.affiliation: Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan, China.
authors.forename: Cheuk-Kwan
authors.initials: CK
authors.lastname: Sun
authors.affiliation: Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan, China.
authors.forename: Hsueh-Wen
authors.initials: HW
authors.lastname: Chang
authors.affiliation: Division of Cardiology, Department of Internal Medicine.
authors.forename: Yen-Yi
authors.initials: YY
authors.lastname: Zhen
authors.affiliation: Division of Thoracic and Cardiovascular Surgery, Department of Surgery.
authors.forename: Fan-Yen
authors.initials: FY
authors.lastname: Lee
authors.affiliation: Division of Cardiology, Department of Internal Medicine.|Institute for Translational Research in Biomedicine.|Center for Shock Wave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, China.|Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan, China.|Department of Nursing, Asia University, Taichung, 41354, Taiwan, China.
authors.forename: Hon-Kan
authors.initials: HK
authors.lastname: Yip
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001011:Aorta / Q000473:pathology / Q000503:physiopathology; D003251:Constriction, Pathologic / Q000150:complications; D015870:Gene Expression; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D000072356:Parenchymal Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000975:Antioxidants; D009842:Oligopeptides; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide