title: Reversible inhibition of vasoconstriction by thiazolidinediones related to PI3K/Akt inhibition in vascular smooth muscle cells.
abstract: Thiazolidinediones (also referred to as glitazones), agonists for Peroxisome Proliferator-Activated Receptor gamma (PPARγ), are used for treating type 2 diabetes mellitus, where they decrease insulin resistance and 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 thiazolidinediones, by affecting the PI3K/Akt pathway, may influence vascular physiology. Isolated rat femoral arteries segments were mounted in a wire myograph and challenged with 100mM 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 PPARγ antagonist) or by N(G)-nitro-L-arginine (LNNA, an inhibitor of NO biosynthesis). Analysis of phospho-Akt (ser 473) in lysates from rat arteries (by immunoblot) revealed that thiazolidinediones, LY294002 and 10-DEBC, at the same concentration and kinetics inhibiting vasoconstriction, produced a similar decrease of Akt phosphorylation. PI3K/Akt pathway therefore appears to be an important, fast acting, modulator of contraction of vascular smooth muscle. Thiazolidinediones 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 in diabetic patients.
authors.affiliation: Department of Clinical and Molecular Biomedicine, Catania University, Catania, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Sinagra
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tamburella
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Urso
authors.forename: Ilias
authors.initials: I
authors.lastname: Siarkos
authors.forename: Filippo
authors.initials: F
authors.lastname: Drago
authors.forename: Claudio
authors.initials: C
authors.lastname: Bucolo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Salomone
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002839:Chromans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005263:Femoral Artery; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D019335:Nitroarginine / Q000494:pharmacology; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077205:Pioglitazone; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D000813:Anilides; D002839:Chromans; D004791:Enzyme Inhibitors; D019335:Nitroarginine; D047495:PPAR gamma; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077205:Pioglitazone; D051057:Proto-Oncogene Proteins c-akt; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D000077288:Troglitazone; C457499:2-chloro-5-nitrobenzanilide