| Phosphatidylinositol 3-kinase-δ up-regulates L-type Ca2+ currents and increases vascular contractility in a mouse model of type 1 diabetes. | |
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MedLine Citation:
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PMID: 20942845 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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J F Pinho; M A A Medeiros; L S A Capettini; B A Rezende; P P Campos; S P Andrade; S F Cortes; J S Cruz; V S Lemos |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: British journal of pharmacology Volume: 161 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-08 Completed Date: 2011-05-18 Revised Date: 2011-12-21 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1458-71 Citation Subset: IM |
Affiliation:
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Department of Physiology and Biophysics, ICB, Federal University of Minas Gerais, Belo Horizonte, Brazil. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Aorta / physiopathology Calcium / metabolism Calcium Channels, L-Type / metabolism* Diabetes Mellitus, Experimental / metabolism*, physiopathology Diabetes Mellitus, Type 1 / metabolism*, physiopathology Male Mice Mice, Inbred C57BL Muscle Contraction Muscle, Smooth, Vascular / physiopathology Myocytes, Smooth Muscle / physiology Patch-Clamp Techniques Phosphatidylinositol 3-Kinases / antagonists & inhibitors, metabolism* Receptors, Adrenergic, alpha-1 / metabolism Signal Transduction Up-Regulation Vasoconstriction Vasodilation |
| Chemical | |
Reg. No./Substance:
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0/Calcium Channels, L-Type; 0/Cav1.2 protein, mouse; 0/Receptors, Adrenergic, alpha-1; 7440-70-2/Calcium; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.1.137/Pik3cd protein, mouse |
| Comments/Corrections | |
Comment In:
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Br J Pharmacol. 2010 Dec;161(7):1455-7
[PMID:
20726982
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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