title: Simvastatin attenuates pulmonary vascular remodelling by down-regulating matrix metalloproteinase-1 and -9 expression in a carotid artery-jugular vein shunt pulmonary hypertension model in rats.
abstract: OBJECTIVE
  It remains controversial as to whether simvastatin has a beneficial effect on pulmonary artery hypertension. This study aimed to explore the efficacy of simvastatin on haemodynamic changes, pulmonary vascular remodelling and expression of matrix metalloproteinase-1 and -9 (MMP-1,9) in a carotid artery-jugular vein (CA-JV) shunt pulmonary artery hypertension (PAH) model in rats.
  
  
  METHODS
  Thirty-six Sprague-Dawley rats were randomized into three groups: Control group, CA-JV group, and Treatment group. A pre-tricuspid systemic-pulmonary shunt from the left common carotid artery to the external jugular vein was established on the CA-JV and Treatment groups, but only ligations of both vessels were performed in Control group. Simvastatin (4 mg/kg/d) was administered to the Treatment group, and placebo to the CA-JV group. Twelve weeks later, the animals underwent a haemodynamic evaluation, followed by pulmonary tissue sampling for morphometry, quantitative real-time PCR and Western blot analysis.
  
  
  RESULTS
  By week 12, rats in the CA-JV group had higher right ventricular systolic pressure (RVSP), medial area/total area (MA/TA) and percentage of fibrous tissue (F%) than those in the Control group. These changes were associated with up-regulation of MMP-1,9 mRNA and increased expression of MMP-1,9 proteins. Pretreatment with simvastatin decreased the shunt-induced RVSP, MA/TA and F% in pulmonary arteries. In addition, lung MMP-1,9 mRNA and proteins levels decreased toward normal levels in simvastatin-treated rats.
  
  
  CONCLUSIONS
  Simvastatin ameliorated the structural and functional derangements of pulmonary arterioles caused by the CA-JV shunt, partly associated with the suppression of up-regulated MMP-1, as well as MMP-9. Simvastatin may play a role in the treatment of systemic-pulmonary shunt-induced PAH diseases, such as congenital heart disease.
authors.affiliation: Department of Paediatric and Congenital Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Yao
authors.forename: Mai
authors.initials: M
authors.lastname: Xiong
authors.forename: Bing
authors.initials: B
authors.lastname: Tang
authors.forename: Guangxian
authors.initials: G
authors.lastname: Chen
authors.forename: Mengya
authors.initials: M
authors.lastname: Liang
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Ma
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wang
authors.forename: Zhongkai
authors.initials: Z
authors.lastname: Wu
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002339:Carotid Arteries / Q000601:surgery; D004195:Disease Models, Animal; D015536:Down-Regulation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007601:Jugular Veins / Q000601:surgery; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; C576840:MMP1 protein, rat; D020781:Matrix Metalloproteinase 1