on November 14, 2002
Arteriosclerosis, Thrombosis, and Vascular Biology. 2002
Published online before print November 14, 2002, doi: 10.1161/01.ATV.0000047447.67827.CD
Published online before print November 14, 2002, doi: 10.1161/01.ATV.0000047447.67827.CD
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Submitted on October 14, 2002
Accepted on October 30, 2002
Effect of Peroxisome Proliferator-Activated Receptor-
and -
Activators on Vascular Remodeling in Endothelin-Dependent Hypertension
Marc Iglarz ;
From the CIHR Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
* To whom correspondence should be addressed. E-mail: schiffe{at}ircm.qc.ca.
Objective—Peroxisome proliferator-activated receptors (PPARs) may modulate in vitro the vascular production of vasoactive peptides such as endothelin-1 (ET-1). Thus, we investigated in vivo the interaction between PPARs and ET-1 in deoxycorticosterone acetate (DOCA)-salt rats that overexpress vascular ET-1.
Methods and Results—Unilaterally nephrectomized 16-week-old Sprague-Dawley rats (Uni-Nx) were divided into 4 groups (n=6 each): control group, DOCA-salt group, DOCA-salt+PPAR- activator (rosiglitazone, 5 mg · kg-1 · d-1), or DOCA-salt+PPAR-
activator (fenofibrate, 100 mg · kg-1 · d-1). Systolic blood pressure was significantly increased in the DOCA-salt group (240±11 vs 121±2 mm Hg in Uni-Nx, P<0.01). Progression of hypertension was partially prevented by coadministration of rosiglitazone (172±3 mm Hg vs DOCA-salt, P<0.05) but not by fenofibrate. Both PPAR activators abrogated the increase in prepro-ET-1 mRNA content in the mesenteric vasculature of DOCA-salt rats. The media-to-lumen ratio was increased in DOCA-salt rats (10.3±0.9% vs 4.9±0.5% in Uni-Nx rats, P<0.01). Rosiglitazone and fenofibrate prevented the hypertrophic remodeling observed in DOCA-salt rats without affecting vascular stiffness. Rosiglitazone but not fenofibrate prevented endothelial dysfunction in pressurized mesenteric arteries. Finally, both rosiglitazone and fenofibrate prevented the vascular increase in superoxide anion production induced in DOCA-salt animals.
Conclusions—PPAR- and - activators were able to modulate endogenous production of ET-1 and had beneficial vascular effects in endothelin-dependent hypertension.
Key words: PPAR activators • rosiglitazone • fenofibrate • resistance arteries • DOCA-salt
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