Title

 

Authors

Ilias Siarkos, Tiziana Sinagra, Alessandra Tamburella, Vincenzo Urso, Filippo Drago, Salvatore Salomone

Dipartimento di Biomedicina Molecolare e Clinica – Sez. Farmacologia e Biochimica
Università di Catania

 

Abstract

Glitazones (thiazolidinediones) are agonists for Peroxisome Proliferator Activator Receptorsgamma(PPARγ), used for treating type 2 diabetes mellitus, where they decrease insulin resistanceand cardiovascular risk. Compounds bearing the thiazolidinedione structure have also been shown to inhibit Phosphoinositide 3-kinase (PI3K). Here we tried to elucidate the poorly defined role of PI3K/Akt in the physiology of vascular smooth muscle cell contraction and tested the hypothesis that glitazones, by affecting the PI3K/Aktpathway, may impact on vascular physiology. Isolated rat femoral arteries segments were mounted in a wire myograph and challenged with 100 mM KCl or phenylephrine (PE), in the absence or presence of troglitazone, rosiglitazone, pioglitazone, LY294002 (PI3K inhibitor) and 10-DEBC (Akt inhibitor). All these compounds dose-dependently inhibited vasoconstriction to KCl or PE; their effect was reversible (after 60-120 min washout) and not affected by GW9662 (a PPARγantagonist) or by N^G-nitro-L-arginine (LNNA, an inhibitor of NO biosynthesis). Analysis of Akt in lysates from femoral arteries (by immunoblot) revealed that glitazones, at the same concentration inhibiting vasoconstriction, produced a decrease of Akt phosphorylation. PI3K/Akt pathway therefore appears to be an important, fast acting, modulator of contraction of vascular smooth muscle. Glitazones decrease vasoconstriction of isolated vessels possibly by inhibiting PI3K/Akt pathway. Such an effect of glitazones, if occurring in vivo, may impact cardiovascular syndromes related to vasospasm.