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Effects of PPAR- ligands on vascular smooth muscle marker expression in hypertensive and normal arteries

Departments of ¹Internal Medicine and ²Physiology, University of Michigan Medical School, Ann Arbor, Michigan; and ³Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan

Submitted 28 June 2004 ; accepted in final form 31 August 2004

Having previously demonstrated that glucose transporter-4 (GLUT4) expression was reduced in aortas and carotid arteries of deoxycorticosterone acetate (DOCA) salt-hypertensive rats, we hypothesized that troglitazone (TG), through activation of peroxisome proliferator-activated receptor- (PPAR-), would stabilize GLUT4 expression and possibly preserve the differentiated phenotype in vascular smooth muscle cells. In DOCA salt-hypertensive rats treated with TG (100 mg/day), there was a significant (P < 0.001) decrease in systolic blood pressure (BP; 149.9 ± 4.4 mmHg) compared with the untreated DOCA salt-hypertensive rats (202.2 ± 10.34 mmHg). Separate trials with rosiglitazone (RS; 3 mg/day) demonstrated a significant (P < 0.001) decrease in BP (DOCA salt, 164.2 ± 9.8 vs. DOCA-RS, 124.9 ± 3.7 mmHg) comparable to that with TG. Expression of GLUT4, h-caldesmon, and smooth muscle myosin heavy chain SM2 was significantly decreased in aortas of DOCA salt-hypertensive rats and was reversed by TG to levels similar to those in aortas of sham-treated rats. TG (50 µM) induced GLUT4 and h-caldesmon expression in 24-h culture of explanted carotid arteries of DOCA salt-hypertensive rats, and the endogenous PPAR- ligand 15-deoxy-^12–14-prostaglandin J₂ (PGJ₂; 20 µM) and TG (50 µM) similarly increased GLUT4, h-caldesmon, and SM2 protein expression in explanted aortas. The expression of activated, phosphorylated Akt was increased by PGJ₂ and TG with no significant effect on total Akt levels. Inhibition of phosphorylated Akt expression using the phosphatidylinositol 3-kinase inhibitor LY-294002 (16 µM) abrogated the increased expression of h-caldesmon and SM2. These data demonstrate that PPAR- agonists maintain or induce expression of markers of the contractile phenotype independently of their effects on hypertension, and that this effect may be mediated through activation of phosphatidylinositol 3-kinase/Akt.

hypertension; peroxisome proliferator-activated receptor-; h-caldesmon; glucose transporter isoform-4

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