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(Circulation. 2001;103:319.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Myocardial Fibrosis in DOCA-Salt Hypertensive Rats
Effect of Endothelin ETA Receptor Antagonism
From the Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Montréal, Québec, Canada.
Correspondence to Ernesto L. Schiffrin, MD, PhD, FRCPC, Clinical Research Institute of Montreal, 110, Avenue des Pins Ouest, Montréal, Québec, Canada H2W 1R7. E-mail schiffe{at}IRCM.qc.ca
Background—To test the hypothesis that endothelin-1 contributes to cardiac fibrosis, cardiac collagen deposition was studied in deoxycorticosterone acetate–salt (DOCA-salt) hypertensive rats, in which the endothelin system is activated. The effects of the ETA-selective endothelin receptor antagonist A-127722 were evaluated.
Methods and Results—A-127722 (30 mg/kg per day) was administered for 4 weeks. Myocardial fibrosis was evaluated after Sirius red F3BA staining. Systolic blood pressure was 103±1.6 mm Hg in unilaterally nephrectomized rats (Uni-Nx), 202±3.2 mm Hg in DOCA-salt rats (P<0.01 versus Uni-Nx), and 182±3.1 mm Hg in ETA antagonist–treated DOCA-salt rats (P<0.01 versus DOCA-salt or Uni-Nx). In DOCA-salt rats, interstitial and perivascular collagen density was increased in the subendocardial and midmyocardial regions of the left ventricle (3- to 4-fold, P<0.05), whereas in subepicardial myocardium, the increase was predominantly perivascular. The ETA antagonist prevented cardiac fibrosis in DOCA-salt rats. Procollagen I and III mRNA, which were increased in hearts of DOCA-salt rats, were normalized by ETA antagonist treatment. TGF-ß1 mRNA and TGF-ß1 protein increased at 1 week in DOCA-salt rats and were lowered in ETA antagonist–treated rats.
Conclusions—ETA receptor–mediated collagen deposition in hearts of DOCA-salt rats results from increased procollagen synthesis associated with an initial increment in expression of TGF-ß1. These results support the hypothesis of a role for endothelin-1 in cardiac collagen deposition in mineralocorticoid hypertension, which may have pathophysiological and pharmacological implications in hypertensive heart disease.
Key Words: collagen • myocardium • growth substances
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