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ligands on vascular smooth muscle marker expression in hypertensive and normal arteries
* To whom correspondence should be addressed. E-mail: katkins{at}umich.edu.
Having previously demonstrated that glucose transporter 4 (GLUT4) expression was reduced in aortae and carotid arteries of deoxycorticosterone acetate-salt (DOCA) hypertensive rats, we hypothesized that troglitazone (TG), through activation of PPAR
, would stabilize GLUT4 expression, possibly preserving the differentiated phenotype in vascular smooth muscle cells. In DOCA-salt rats treated with TG (100mg/day) there was a significant (p<0.001) decrease in systolic blood pressure (BP) (149.9±4.4 mmHg) compared to the untreated DOCA-salt 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) comparable to that with TG. Expression of GLUT4, h-caldesmon, and smooth muscle myosin heavy chain, SM2, was significantly decreased in aortae of DOCA-salt rats and was reversed by TG to levels similar to those in aortae of Sham rats. TG (50 µM) induced GLUT4 and h-caldesmon expression in 24h culture of explanted carotid arteries of DOCA-salt rats and the putative 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 aortae. The expression of activated, phosphorylated Akt was increased by PGJ2 and TG with no significant effect on total Akt. Inhibition of pAkt expression using LY294002 (16 µM), a phosphtidylinositol-3-kinase inhibitor, 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 PI3-kinase/Akt.
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