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Br J Pharmacol. 2010 Dec;161(7):1458-71. doi: 10.1111/j.1476-5381.2010.00955.x.

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

Author information

1
Department of Physiology and Biophysics, ICB, Federal University of Minas Gerais, Belo Horizonte, Brazil.

Abstract

BACKGROUND AND PURPOSE:

Vasculopathies represent the main cause of morbidity and mortality in diabetes. Vascular malfunctioning in diabetes is associated with abnormal vasoconstriction and Ca(2+) 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 Ca(2+) channels (Ca(V) 1.2). In the present work, we investigated the involvement of PI3K signalling in regulating Ca(2+) current through Ca(V) 1.2 (I(Ca,L) ) and vascular dysfunction in a mouse model of type I diabetes.

EXPERIMENTAL APPROACH:

Changes in isometric tension were recorded on myograph. Ca(2+) currents in freshly dissociated mice aortic SMCs were measured using the whole-cell patch-clamp technique. Antisense techniques were used to knock-down the PI3Kδ 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 I(Ca,L) was also greatly augmented. PI3Kδ expression, but not PI3Kα, PI3Kβ, PI3Kγ, was increased in diabetic aortas and treatment of vessels with a selective PI3Kδ inhibitor normalized I(Ca,L) and contractile response of diabetic vessels. Moreover, knock-down of PI3Kδin vivo decreased PI3Kδ expression and normalized I(Ca,L) and contractile response of diabetic vessels ex vivo.

CONCLUSIONS AND IMPLICATIONS:

Phosphatidylinositol 3-kinase δ was essential to the increased vascular contractile response in our model of type I diabetes. PI3Kδ signalling was up-regulated and most likely accounted for the increased I(Ca,L,) leading to increased vascular contractility. Blockade of PI3Kδ may represent a novel therapeutic approach to treat vascular dysfunction in diabetic patients.

PMID:
20942845
PMCID:
PMC3010560
DOI:
10.1111/j.1476-5381.2010.00955.x
[Indexed for MEDLINE]
Free PMC Article

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