title: Cardiac fibrosis occurs early and involves endothelin and AT-1 receptors in hypertension due to endogenous angiotensin II.
abstract: OBJECTIVE
  We investigated if endothelin (ET)-1 and the renin-angiotensin-aldosterone system play a role in cardiac fibrosis.
  
  
  BACKGROUND
  Angiotensin II (Ang II) can induce cardiac fibrosis, but the underlying mechanisms are incompletely understood.
  
  
  METHODS
  Four-week-old transgenic (mRen2)27 rat (TGRen2) received for four weeks a placebo, the mixed ET(A)/ET(B) endothelin receptor antagonist bosentan, the angiotensin II type I receptor (AT-1) antagonist irbesartan, the ET(A) endothelin receptor antagonist BMS-182874, and a combined treatment with irbesartan plus BMS-182874. We measured collagen density on Sirius red-stained serial sections of the left ventricle (LV) with a photomicroscope equipped with specific software and assessed the gene expression of procollagen alpha1(I), atrial natriuretic peptide (ANP), transforming growth factor-beta 1 (TGFbeta1), endothelin converting enzyme, and ET(B) receptor.
  
  
  RESULTS
  In the placebo group, hypertension was associated with LV hypertrophy and cardiac fibrosis (LV weight: 4.0 +/- 0.3 mg/g body weight; collagen density: 2.21 +/- 0.16%), which were all prevented with irbesartan (2.3 +/- 0.1, 1.30 +/- 0.13, p < 0.001), but not with BMS-182874 (4.0 +/- 0.2, 2.41 +/- 0.22). Bosentan also prevented fibrosis (1.39 +/- 0.18) but not hypertension and LV hypertrophy (3.38 +/- 0.27). Combined irbesartan and BMS-182874 treatment prevented LV hypertrophy (2.9 +/- 0.1) but not fibrosis (2.52 +/- 0.16). Collagen density correlated (r = 0.414, p < 0.05) with plasma aldosterone levels. In TGRen2 with LV hypertrophy, the gene expression of ANP and ET(B) but not that of TGFbeta1 and procollagen alpha1(I) was increased.
  
  
  CONCLUSIONS
  In Ang II-dependent hypertension, cardiac fibrosis was associated with LV hypertrophy and was hindered by both mixed ET(A)/ET(B) blockade and AT-1 blockade. Only the latter treatment prevented both hypertension and LV hypertrophy. Thus, there is a dissociation between the mechanisms of cardiac fibrosis and hypertension, which do and do not entail ET-1, respectively.
authors.affiliation: Department of Clinical Methodology and Clinical-Surgical Technologies, University of Bari, Bari, Italy.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Seccia
authors.forename: Anna S
authors.initials: AS
authors.lastname: Belloni
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kreutz
authors.forename: Martin
authors.initials: M
authors.lastname: Paul
authors.forename: Gastone G
authors.initials: GG
authors.lastname: Nussdorfer
authors.forename: Achille C
authors.initials: AC
authors.lastname: Pessina
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Rossi
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D000077300:Bosentan; D009202:Cardiomyopathies / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D003619:Dansyl Compounds / Q000494:pharmacology; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000187:drug effects / Q000502:physiology*; D005355:Fibrosis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D006973:Hypertension / Q000139:chemically induced* / Q000150:complications / Q000503:physiopathology*; D000077405:Irbesartan; D008297:Male; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000009:adverse effects*
chemical_list: D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D003619:Dansyl Compounds; D019332:Endothelin-1; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D011956:Receptors, Cell Surface; D013449:Sulfonamides; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; D000077405:Irbesartan; D000077300:Bosentan