Effect of Peroxisome Proliferator–Activated Receptor-α and -γ Activators on Vascular Remodeling in Endothelin-Dependent Hypertension

Abstract

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 (nϭ6 each): control group, DOCA-salt group, DOCA-saltϩPPAR-␥ activator (rosiglitazone, 5 mg · kg). Systolic blood pressure was significantly increased in the DOCA-salt group (240Ϯ11 vs 121Ϯ2 mm Hg in Uni-Nx, PϽ0.01). Progression of hypertension was partially prevented by coadministration of rosiglitazone (172Ϯ3 mm Hg vs DOCA-salt, PϽ0.05) 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 (10.3Ϯ0.9% vs 4.9Ϯ0.5% in Uni-Nx rats, PϽ0.01). 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 Ⅲ rosiglitazone Ⅲ fenofibrate Ⅲ resistance arteries Ⅲ DOCA-salt P eroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated transcription factors that have recently been found to be involved in the homeostasis of vascular biology. 1 Indeed, PPAR-␣ and -␥ isoforms have been characterized in multiple vascular cell types in rats and humans. [2][3][4][5][6] Moreover, PPAR activators prevent in vitro vascular smooth muscle cell growth 4 and inflammatory response 5 and also induce apoptosis, 6 suggesting at least a potential role in vascular remodeling.A recent study from our laboratory demonstrated that both PPAR-␣ and -␥ activators prevent vascular remodeling in angiotensin II-infused rats. 7 As angiotensin II, endothelin-1 (ET-1) is a potent vasoconstrictor. It is produced within the vascular wall and plays a critical role in vascular hypertrophy in many models of hypertension, such as deoxycorticosterone acetate (DOCA)-salt rats or stroke-prone spontaneously hypertensive rats. 8 Indeed, in those models of hypertension in which ET-1 plays a vasoconstrictor role, ET-1 was overexpressed in the vessel wall, and systolic blood pressure (SBP) was lowered by endothelin receptor antagonists. 8 Moreover, in these experimental models, ET-1 receptor antagonists also regressed vascular growth and inflammation and improved endothelial dysfunction. 8,9 Interestingly, PPAR-␥ activators are able to suppress ET-1 secretion from endothelial and vascular smo...

Peroxisome Proliferator–Activated Receptor γ Regulates Angiotensin II–Stimulated Phosphatidylinositol 3-Kinase and Mitogen-Activated Protein Kinase in Blood Vessels In Vivo

“…We and others have shown previously that in models of experimental hypertension, TZDs are antihypertensive and reverse structural, functional, and molecular changes in blood vessels. 4,26,27 The mechanisms of these potentially beneficial cardiovascular effects are in part clarified in the present study. PPAR-␥ activation negatively modulated Ang II-induced growth-promoting intracellular signaling pathways, such as MAPK and PI3K, and their target protein, such as 4E-BP1.…”

Rosiglitazone prevents the progression of renal injury in DOCA-salt hypertensive rats

“…It has antiinflammatory and anti-fibrotic effects in nondiabetic renal disease, 7 and an anti-hypertensive effect. 8 Deoxycorticosterone acetate (DOCA)-salt hypertensive rat is a well known, established model of mineralocorticoid hypertension with renal dysfunction. Although mineralocorticoid is traditionally known to promote sodium retention, recent evidence indicates that it causes oxidative stress, 9 and stimulates inflammation and fibrosis by activating transcription factors such as nuclear factor k-B (NF-kB) and activating protein-1.…”

PPARα ligand clofibrate ameliorates blood pressure and vascular reactivity in spontaneously hypertensive rats

“…At the same time, reduced vasoconstriction response to endogenous vasoconstrictor in SHR by clofibrate propose that clofibrate-mediated induction of PPARα may have a role on PE, AII, TxA 2 and ET-1. This notion is corroborated by studies that showed reduced vasoconstrictor activity of these endogenous vasoconstrictors after activation of PPARα [28][29][30] . Additionally, Jonkers et al reported a reduction in blood pressure in patients treated with bezafibrate (a PPARα agonist) and correlated that with an improvement in endothelial function and increased in plasma cGMP [31] .…”

“…In the present report we have provided further in vivo evidence for the beneficial effect of clofibrate in blood pressure reduction through normalization of vascular responses to vasoconstrictors in SHR. Similarly, Iglarz et al reported in DOCA-salt-treated rats, that both fenofibrate and rosiglitazone modulated endogenous production of ET-1 and provided beneficial vascular effect in endothelin-dependent hypertension without improving endothelial dysfunction [29] . This data confirms potential benefit of clofibrate in blood pressure regulation in both endotheliumdependent as well as endothelium-independent mechanisms.…”