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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 39; no. 2, Part 2 Suppl; pp. 679 - 684
• Main Authors: Ammarguellat, Fatima Z, Gannon, Philippe O, Amiri, Farhad, Schiffrin, Ernesto L
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.02.2002; Hagerstown, MD Lippincott
• Subjects: Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Experimental diseases; Medical sciences; Hypertension; Endothelin; Prognosis; Rat; Enzyme; Pathogenesis; Rodentia; Cardiovascular disease; Metalloendopeptidases; Inflammation; Salt overload; Fibronectin; Gelatinase B; Gelatinase A; Desoxycortone; Vascular remodeling; Peptidases; Vertebrata; Mammalia; Animal; Fibrosis; Hydrolases; Apoptosis
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/hy0202.103481

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 NFκB, 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 ETA 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 ETA 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-κB 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 ETA 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 ETA antagonism.