title: Role of chymase in cigarette smoke-induced pulmonary artery remodeling and pulmonary hypertension in hamsters.
abstract: BACKGROUND
  Cigarette smoking is an important risk factor for pulmonary arterial hypertension (PAH) in chronic obstructive pulmonary disease (COPD). Chymase has been shown to function in the enzymatic production of angiotensin II (AngII) and the activation of transforming growth factor (TGF)-beta1 in the cardiovascular system. The aim of this study was to determine the potential role of chymase in cigarette smoke-induced pulmonary artery remodeling and PAH.
  
  
  METHODS
  Hamsters were exposed to cigarette smoke; after 4 months, lung morphology and tissue biochemical changes were examined using immunohistochemistry, Western blotting, radioimmunoassay and reverse-transcription polymerase chain reaction.
  
  
  RESULTS
  Our results show that chronic cigarette smoke exposure significantly induced elevation of right ventricular systolic pressures (RVSP) and medial hypertrophy of pulmonary arterioles in hamsters, concurrent with an increase of chymase activity and synthesis in the lung. Elevated Ang II levels and enhanced TGF-beta1/Smad signaling activation were also observed in smoke-exposed lungs. Chymase inhibition with chymostatin reduced the cigarette smoke-induced increase in chymase activity and Ang II concentration in the lung, and attenuated the RVSP elevation and the remodeling of pulmonary arterioles. Chymostatin did not affect angiotensin converting enzyme (ACE) activity in hamster lungs.
  
  
  CONCLUSIONS
  These results suggest that chronic cigarette smoke exposure can increase chymase activity and expression in hamster lungs. The capability of activated chymase to induce Ang II formation and TGF-beta1 signaling may be part of the mechanism for smoking-induced pulmonary vascular remodeling. Thus, our study implies that blockade of chymase might provide benefits to PAH smokers.
authors.affiliation: Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, and Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Su-Xia
authors.initials: SX
authors.lastname: Han
authors.forename: Shang-Fu
authors.initials: SF
authors.lastname: Zhang
authors.forename: Yun-Ye
authors.initials: YY
authors.lastname: Ning
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Ya-Juan
authors.initials: YJ
authors.lastname: Chen
authors.forename: Guang-Ming
authors.initials: GM
authors.lastname: He
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.forename: Jin
authors.initials: J
authors.lastname: An
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Zhang
authors.forename: Fu-Qiang
authors.initials: FQ
authors.lastname: Wen
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D053818:Chymases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D004195:Disease Models, Animal; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D006984:Hypertrophy; D007118:Immunoassay; D007150:Immunohistochemistry; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation; D016278:Ventricular Function, Right; D017725:Ventricular Pressure
chemical_list: D009842:Oligopeptides; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; C002101:chymostatin; D053818:Chymases