Phosphatidylinositol 3-kinase-[delta] up-regulates L-type Ca2+ currents and increases vascular contractility in a mouse model of type 1 diabetes

• Published in: British journal of pharmacology Vol. 161; no. 7; p. 1458
• Main Authors: Pinho, JF, Medeiros, MAA, Capettini, LSA, Rezende, BA, Campos, PP, Andrade, SP, Cortes, SF, Cruz, JS, Lemos, VS
• Format: Journal Article
• Language: English
• Published: London Blackwell Publishing Ltd 01-12-2010
• Subjects: Diabetes; Muscular system; Rodents
• DOI: 10.1111/j.1476-5381.2010.00955.x
• EISSN: 1476-5381
• ISSN: 0007-1188

BACKGROUND AND PURPOSE Vasculopathies represent the main cause of morbidity and mortality in diabetes. Vascular malfunctioning in diabetes is associated with abnormal vasoconstriction and Ca2+ handling by smooth muscle cells (SMC). Phosphatidylinositol 3-kinases (PI3K) are key mediators of insulin action and have been shown to modulate the function of voltage-dependent L-type Ca2+ channels (CaV1.2). In the present work, we investigated the involvement of PI3K signalling in regulating Ca2+ current through CaV1.2 (ICa,L) and vascular dysfunction in a mouse model of type I diabetes. EXPERIMENTAL APPROACH Changes in isometric tension were recorded on myograph. Ca2+ currents in freshly dissociated mice aortic SMCs were measured using the whole-cell patch-clamp technique. Antisense techniques were used to knock-down the PI3K[delta] isoform. KEY RESULTS Contractile responses to phenylephrine and KCl were strongly enhanced in diabetic aorta independent of a functional endothelium. The magnitude of phenylephrine-induced ICa,L was also greatly augmented. PI3K[delta] expression, but not PI3K[alpha], PI3K[beta], PI3K[gamma], was increased in diabetic aortas and treatment of vessels with a selective PI3K[delta] inhibitor normalized ICa,L and contractile response of diabetic vessels. Moreover, knock-down of PI3K[delta]in vivo decreased PI3K[delta] expression and normalized ICa,L and contractile response of diabetic vessels ex vivo. CONCLUSIONS AND IMPLICATIONS Phosphatidylinositol 3-kinase [delta] was essential to the increased vascular contractile response in our model of type I diabetes. PI3K[delta] signalling was up-regulated and most likely accounted for the increased ICa,L, leading to increased vascular contractility. Blockade of PI3K[delta] may represent a novel therapeutic approach to treat vascular dysfunction in diabetic patients. LINKED ARTICLE This article is commented on by Sturek, pp. 1455-1457 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00997.x [PUBLICATION ABSTRACT]