title: Simvastatin alleviates cardiac fibrosis induced by infarction via up-regulation of TGF-β receptor III expression.
abstract: OBJECTIVE
  Statins decrease heart disease risk, but their mechanisms are not completely understood. We examined the role of the TGF-β receptor III (TGFBR3) in the inhibition of cardiac fibrosis by simvastatin.
  
  
  METHODS
  Myocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery in mice given simvastatin orally for 7 days. Cardiac fibrosis was measured by Masson staining and electron microscopy. Heart function was evaluated by echocardiography. Signalling through TGFBR3, ERK1/2, JNK and p38 pathways was measured using Western blotting. Collagen content and cell viability were measured in cultures of neonatal mouse cardiac fibroblasts (NMCFs). Interactions between TGFBR3 and the scaffolding protein, GAIP-interacting protein C-terminus (GIPC) were detected using co-immunoprecipitation (co-IP). In vivo, hearts were injected with lentivirus carrying shRNA for TGFBR3.
  
  
  RESULTS
  Simvastatin prevented fibrosis following MI, improved heart ultrastructure and function, up-regulated TGFBR3 and decreased ERK1/2 and JNK phosphorylation. Simvastatin up-regulated TGFBR3 in NMCFs, whereas silencing TGFBR3 reversed inhibitory effects of simvastatin on cell proliferation and collagen production. Simvastatin inhibited ERK1/2 and JNK signalling while silencing TGFBR3 opposed this effect. Co-IP demonstrated TGFBR3 binding to GIPC. Overexpressing TGFBR3 inhibited ERK1/2 and JNK signalling which was abolished by knock-down of GIPC. In vivo, suppression of cardiac TGFBR3 abolished anti-fibrotic effects, improvement of cardiac function and changes in related proteins after simvastatin.
  
  
  CONCLUSIONS
  TGFBR3 mediated the decreased cardiac fibrosis, collagen deposition and fibroblast activity, induced by simvastatin, following MI. These effects involved GIPC inhibition of the ERK1/2/JNK pathway.
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Duan
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Muge
authors.initials: M
authors.lastname: Qile
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Zengyan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Qiu
authors.affiliation: Departments of Clinical Pharmacy and Cardiology, The 2nd Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, Heilongjiang, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Chu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004452:Echocardiography; D005355:Fibrosis / Q000188:drug therapy* / Q000473:pathology; D055785:Gene Knockdown Techniques; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D011509:Proteoglycans / Q000096:biosynthesis*; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis*; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C115271:Gipc1 protein, mouse; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; C071736:betaglycan; D019821:Simvastatin