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(Hypertension. 2002;39:679.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Fibrosis, Matrix Metalloproteinases, and Inflammation in the Heart of DOCA-Salt Hypertensive Rats: Role of ET_A Receptors

Fatima Z. Ammarguellat; Philippe O. Gannon; Farhad Amiri; Ernesto L. Schiffrin

From the Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Quebec, 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

In deoxycorticosterone acetate (DOCA)-salt hypertension, the endothelin-1 system is activated and plays a role in cardiac fibrosis. Remodeling of extracellular matrix (ECM) may lead to interstitial fibrosis, which may contribute to heart failure. Imbalance in synthesis and degradation of the ECM by matrix metalloproteinases (MMPs) as well as inflammation may play a role in matrix protein deposition and cardiac remodeling in hypertension. We measured expression of the extracellular matrix protein fibronectin, the activity of the gelatinases MMP-2 and MMP-9, the proinflammatory transcription factor NFB, and the adhesion molecules, vascular cell adhesion molecule (VCAM)-1 and platelet-endothelial cell adhesion molecule (PECAM)-1 in hearts of DOCA-salt hypertensive (DS) rats treated or not with the endothelin ET_A antagonist BMS 182874 (BMS). Unilaterally nephrectomized rats (UniNx) were compared with DS rats treated or not with BMS 40 mg/kg/d. Fibronectin deposition was detectable at the first week, and remained elevated thereafter. This increase was abrogated by administration of the ET_A antagonist. Enzymatic activity of gelatinases was increased (P<0.01) in DS compared with control during the first and second week. BMS blocked the increase of MMP-2 and MMP-9 activity at week 1 (P<0.05); MMP activity remained lower than in DS at week 2. NF-B binding activity in DS was higher (P<0.05) than it was in controls during the second week, and was reduced by BMS. The adhesion molecules VCAM-1 and PECAM-1, and the antiapoptotic molecule xIAP were upregulated in the left ventricle of the heart of DS rats and downregulated in the rats treated with the ET_A antagonist. In conclusion, cardiac extracellular remodeling in rats with endothelin-dependent hypertension was associated with increased fibronectin, MMP activity, and upregulation of inflammatory mediators, all of which were reduced by ET_A antagonism.

Key Words: hypertension, mineralocorticoid • myocardium • endothelin • fibronectin • apoptosis

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