کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5843871 | 1127271 | 2011 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Angiotensin II causes endothelial dysfunction via the GRK2/Akt/eNOS pathway in aortas from a murine type 2 diabetic model
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کلمات کلیدی
ANGIIIGTTregulators of G-protein signalingKHsPGF2αGRK2GRKKrebs–Henseleit solutionIRS-1α-ARSTZeNOSvWFGPCRG-protein-coupled receptor - G-پروتئین گیرندهG-protein-coupled receptor kinase - G-پروتئین گیرنده کینازintravenous glucose tolerance test - آزمون تحمل گلوکز داخل وریدیAngiotensin II - آنژیوتانسین دوACh - آهstreptozotocin - استرپتوزوتوسینAcetylcholine - استیل کولینinsulin receptor substrate-1 - انسولین گیرنده زیربخش 1Cardiovascular diseases - بیماری قلبی-عروقی Diabetes mellitus - دیابت قندیVon Willebrand factor - عامل فون ویلبراندDiabetic mice - موش دیابتیsodium nitroprusside - نیتروپروساید سدیمNitric oxide - نیتریک اکسیدPleckstrin Homology - همخوانی Pleckstrinprostaglandin - پروستاگلاندینهاSNP - چندریختی تک-نوکلئوتیدAlpha-adrenergic receptors - گیرنده های آلفا آدرنرژیک
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
داروشناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Nitric oxide (NO) production and endothelial function are mediated via the Akt/eNOS pathway. We investigated the reductions of these mechanism(s) in type 2 diabetes. Diabetic model (nicotinamide + streptozotocin-induced) mice were fed for 4 weeks on a normal diet either containing or not containing losartan, an AT1 R antagonist. Relaxations and NO productions were measured in isolated aortas. G-protein coupled receptor kinase 2 (GRK2) protein levels and activities in the Akt/eNOS signaling-pathway were mainly assayed by Western blotting. Clonidine- and insulin-induced relaxations and NO productions, all of which were significantly decreased in aortas isolated from the diabetics, were normalized by 4 weeks' losartan administration. Plasma angiotensin II (Ang II) and GRK2 protein levels were increased in diabetes, and each was normalized by 4 week's losartan administration. Additionally, there was a direct correlation between the plasma Ang II and aortic GRK2 protein levels. In the diabetics, the clonidine-induced responses (but not the insulin-induced ones) were enhanced by GRK2-inhibitor. Akt phosphorylation was markedly below control in the clonidine-stimulated diabetes. The phosphorylation of Akt at Thr308 was significantly normalized and the phosphorylation of eNOS at Ser1177 tended to be increased by GRK2-inhibitor in the clonidine-stimulated diabetics. Our data suggest that (a) the Akt/eNOS pathway is downstream of GRK2, and that GRK2 inhibits Akt/eNOS activities, and (b) this pathway underlies the impaired NO production seen in type 2 diabetes, in which there are defective phosphorylations of Akt and eNOS that may be caused by an upregulation of GRK2 secondary to a high plasma Ang II level. Inhibitors of GRK2 warrant further investigation as potential new therapeutic agents in diabetes.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Pharmacological Research - Volume 64, Issue 5, November 2011, Pages 535-546
Journal: Pharmacological Research - Volume 64, Issue 5, November 2011, Pages 535-546
نویسندگان
Kumiko Taguchi, Tsuneo Kobayashi, Yasuhiro Takenouchi, Takayuki Matsumoto, Katsuo Kamata,