title: ET-1 from endothelial cells is required for complete angiotensin II-induced cardiac fibrosis and hypertrophy.
abstract: OBJECTIVE
  Hypertensive patients develop cardiac hypertrophy and fibrosis with increased stiffness, contractile deficit and altered perfusion. Angiotensin II (AngII) is an important factor in the promotion of this pathology. The effects of AngII are partly mediated by endothelin-1 (ET-1) and transforming growth factor-β. The exact feature of these pathways and the intercellular communications involved remain unclear. In this study, we explored the role of endothelial cell-derived ET-1 in the development of AngII-induced cardiac fibrosis and hypertrophy.
  
  
  METHODS
  We used mice with vascular endothelial cell specific ET-1 deficiency (VEETKO) and their wild type littermates (WT). Mice were infused for one week with AngII (3.2mg/kg/day, n=12) or vehicle (0.15 mol/L NaCl and 1 mmol/L acetic acid, n=5), using subcutaneous mini-pumps. Hearts were stained with hematoxylin-eosin and masson's trichrome for histology. Cardiac gene expression and protein abundance were measured by Northern Blot, real time PCR and Western Blot.
  
  
  RESULTS
  AngII-induced cardiac hypertrophy, interstitial and perivascular fibrosis were less pronounced in VEETKO mice compared to WT. Blood pressure increased similarly in both genotypes. Expression of connective tissue growth factor, tumor growth factor-β, collagen I and III in response to AngII required endothelial ET-1. Endothelial ET-1 was also necessary to the elevation in protein kinase C δ abundance and ERK1/2 activation. AngII-induced elevation in PKCε abundance was however ET-1 independent.
  
  
  CONCLUSIONS
  This study underscores the significance of ET-1 from the vasculature in the process of AngII-induced cardiac hypertrophy and fibrosis, independently from blood pressure. Endothelial ET-1 represents therefore a possible pharmacological target.
authors.affiliation: Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, Japan.
authors.forename: Suko
authors.initials: S
authors.lastname: Adiarto
authors.forename: Susi
authors.initials: S
authors.lastname: Heiden
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vignon-Zellweger
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakayama
authors.forename: Keiko
authors.initials: K
authors.lastname: Yagi
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Noriaki
authors.initials: N
authors.lastname: Emoto
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D001794:Blood Pressure; D015152:Blotting, Northern; D015153:Blotting, Western; D006332:Cardiomegaly / Q000473:pathology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009206:Myocardium / Q000473:pathology*; D016133:Polymerase Chain Reaction; D051745:Protein Kinase C-delta / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D000804:Angiotensin II; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3