Role of PI3-Kinase in Isoproterenol and IGF-1 Induced ecNOS Activity

Isenović, Esma R.; Muniyappa, Ranganath; Milivojević, Nikola; Rao, Yoshida; Sowers, James R.

doi:10.1006/bbrc.2001.5246

Cited by 37 publications

(29 citation statements)

References 18 publications

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“…5,21 Many stimuli (including insulin, vascular endothelial growth factor, ␤-agonists, and shear-stress signals) regulate NO production by activating eNOS via Ser-1177 phosphorylation through the PI3-kinase/Akt pathway. 10,11,22 When a PI3-K or Akt inhibitor was added in our study, there was no significant difference in the ACh-induced relaxation or in NO x Ϫ /cGMP production, whereas the clonidine-induced and insulin-induced responses were completely abolished by each inhibitor in control aortas. These observations suggest that clonidine-induced and insulin-induced vasorelaxations are regulated by the PI3-K/Akt signal pathway.…”

Section: Discussionmentioning

confidence: 50%

“…Some studies have suggested a role for PI3-K/Akt in the induction of NO in the endothelium by insulin or ␤-agonists, because inhibition of such agonist-induced activations of PI3-K leads to impaired NO availability. 10,11 However, it is not known how (or whether) PI3-K/Akt/eNOS regulation is altered in the impaired endothelium-dependent relaxation seen in type 2 diabetic models.…”

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confidence: 99%

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Impairment of PI3-K/Akt Pathway Underlies Attenuated Endothelial Function in Aorta of Type 2 Diabetic Mouse Model

et al. 2004

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Abstract-The phosphatidylinositol 3-kinase (PI3-K) pathway, which activates serine/threonine protein kinase Akt, enhances endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. We investigated the involvement of the PI3-K/Akt pathway in the relaxation responses to acetylcholine (ACh) and clonidine in a new type 2 diabetic model (streptozotocin plus nicotinamide-induced diabetic mice). Plasma glucose and insulin levels were significantly elevated in our model, and intravenous glucose tolerance tests revealed clear abnormalities in glucose tolerance and insulin responsiveness. Although in our model the ACh-induced relaxation and NO x Ϫ (NO 2 Ϫ ϩNO 3 Ϫ )/cGMP production were unchanged, the clonidine-induced and insulin-induced relaxations and NO x Ϫ /cGMP production were all greatly attenuated. In control mice, the clonidine-induced and insulin-induced relaxations were each abolished by LY294002 and by Wortmannin (inhibitors of PI3-K), and also by Akt-inhibitor treatment. The ACh-induced relaxation was unaffected by such treatments in either group of mice. The expression level of total Akt protein was significantly decreased in the diabetic mice aorta, but those for the p85 and p110␥ subunits of PI3-K were not. The clonidine-induced Ser-473 phosphorylation of Akt through PI3-K was significantly decreased in our model; however, that induced by ACh was not. These results suggest that relaxation responses and NO production mediated via the PI3-K/Akt pathway are decreased in this type 2 diabetic model. This may be a major cause of endothelial dysfunction (and the resulting hypertension) in type 2 diabetes. Key Words: diabetes mellitus Ⅲ hyperinsulinism Ⅲ aorta Ⅲ endothelium-derived relaxing factor Ⅲ nitric oxide N umerous epidemiological studies have indicated that the insulin resistance and hyperinsulinemia associated with type 2 diabetes make important contributions to the development of hypertension and cardiovascular diseases, and impaired endothelium-dependent vasodilation has been described in humans and in animal models of the disease. 1,2 We and others have demonstrated that both aortic endothelial dysfunction and hypertension are present in type 2 spontaneously diabetic (db/db Ϫ/Ϫ ) mice and in fructose-fed insulinresistance mice. [3][4][5][6] Our recent observation that endothelial function and nitric oxide (NO) production are impaired in aortic strips from spontaneously type 2 diabetic GotoKakizaki rats seemed to conflict with our finding that the expressions of the mRNA and protein for endothelial NO synthase (eNOS) were increased in such aortas. 7

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Section: Discussionmentioning

confidence: 50%

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Impairment of PI3-K/Akt Pathway Underlies Attenuated Endothelial Function in Aorta of Type 2 Diabetic Mouse Model

et al. 2004

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“…Many stimuli (including a 2 -agonists, insulin, vascular endothelial growth factor, b-agonists, estrogen, and shear-stress signals) regulate NO production by activating eNOS via Ser-1177 phosphorylation through the PI3-kinase/Akt pathway. [34][35][36][37] We previously found that in the mouse aorta, neither addition of LY294002 [an inhibitor of phosphatidylinositol 3 (PI3)-kinase] nor addtion of Akt inhibitor had any significant effect on the ACh-induced relaxation or on ACh-induced NO x /c-GMP production, whereas the clonidine-and insulin-induced relaxation responses were completely abolished by each of these inhibitors. 21,22) These observations suggest that in mouse aortas exposed to clonidine or insulin, both endothelium-dependent relaxation and NO production may be mediated or regulated by the PI3-kinase/Akt signal pathway.…”

Section: Discussionmentioning

confidence: 99%

“…In endothelial cells, the main signal-transduction pathway for agonist-stimulated eNOS activation depends on Ca 2ϩ /calmodulin/caveolin-1. At the cellular level, there is growing evidence that for some agonists, such as acetylcholine, histamine, and bradykinin, [37][38][39] a rise in intracellular Ca 2ϩ is necessary for NO production. In contrast, as already mentioned, for other stimuli (such as a 2 -agonists, insulin, and estrogen) a rise in Ca 2ϩ is not required, and NO production is activated by eNOS through the PI3-kinase/Akt patway.…”

Section: Discussionmentioning

confidence: 99%

Gender Differences in Vascular Reactivity of Aortas from Streptozotocin-Induced Diabetic Mice

Takenouchi

Kobayashi

Taguchi

et al. 2010

Biological & Pharmaceutical Bulletin

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Diabetes mellitus is a syndrome of disordered metabolism, usually due to a combination of hereditary and environmental causes, resulting in abnormally high blood glucose levels. The two most common forms of diabetes are due to either a diminished production of insulin (type 1) or a diminished response to insulin (type 2). Diabetes is a risk factor in the development of both macro-and microvascular diseases. [1][2][3] Indeed, it increases the incidence of ischemic heart disease, cerebral ischemia, and atherosclerosis, conditions in which endothelial dysfunction plays a role in pathogenesis. One of the most important functions of the endothelium is the production of nitric oxide (NO) in response to various hormonal, mechanical, and chemical stimuli. NO has a variety of effects, including the induction of vascular relaxation. In patients with either type 1 or type 2 diabetes, the forearm blood-flow (dilator) responses to acetylcholine (ACh) are reduced, suggesting endothelial dysfunction. 4,5) In streptozotocin (STZ)-induced diabetic rats or mice, which are models of type 1 diabetes, the endothelium-dependent relaxation induced by ACh is impaired, and reactive oxygen species and polyol products have been suggested to be involved in this impairment.6-9) Moreover, there is evidence that endothelial function is impaired in patients with diabetes mellitus 10,11) in a manner similar to that seen in STZ-treated animals. Thus, STZ-induced diabetic rats and mice may provide models for studies of the underlying causes of endothelial-cell damage in diabetes mellitus, and a means of assessing the contribution of diabetes mellitus to cardiovascular disease states.Gender differences in blood pressure 12) and vascular reactivity [13][14][15][16][17] have been reported in rats and mice. Although in the general (non-diabetic) population, cardiovascular diseases are more frequent in men than in premenopausal women, 18,19) diabetes may produce a greater impairment in the female cardiovascular system, with the result that the above difference between men and premenopausal women disappears in diabetic patients. 20) Although some studies have been carried out on the effects of exogenous sex hormones in diabetes, few studies have compared the influence of diabetes on vascular reactivity between males and females.Against this background, we decided to assess whether there are gender differences in the effects of type 1 diabetes on the endothelium-dependent vascular relaxations to various stimuli. For this, we employed aortas isolated from STZ-induced diabetic mice. Although there have been many reports that male diabetic-model mice or rats exhibit endothelial dysfunction, little is known about gender differences in endothelial function in diabetes, particularly in murine models. That was our rationale for investigating gender differences in vascular reactivity in the aorta using STZ-induced type 1 diabetic-model mice. MATERIALS AND METHODSReagents STZ, clonidine hydrochloride, insulin from porcine pancreas, norepinephrine (NE), and N w -...

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“…More than half of the drugs currently in clinical use target GPCR by either mimicking endogenous GPCR ligands, blocking ligand access to the receptor or by modulating ligand production [14], which also represents the mechanism of action of sympatholytic and sympathomimetic drugs. Agonist-dependent desensitization of GPCR is caused by the phosphorylation of the specific receptor by the GRK family [15][16][17][18]. GRKs have a central catalytic domain flanked by amino-terminal and carboxyl-terminal domains which contain specific regulatory sites (Figure 1) [10].…”

Section: G Protein Related Kinases -General Overviewmentioning

confidence: 99%

State of the art paper The role of G protein coupled receptor kinases in neurocardiovascular pathophysiology

Bojić¹,

Sudar-Milovanović²,

Mikhailidis³

et al. 2012

aoms

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A b s t r a c tIn coronary artery disease the G protein related kinases (GRKs) play a role in desensitization of β-adrenoreceptors (AR) after coronary occlusion. Targeted deletion and lowering of cardiac myocyte GRK-2 decreases the risk of postischemic heart failure (HF). Studies carried out in humans confirm the role of GRK-2 as a marker for the progression of HF after myocardial infarction (MI). The level of GRK-2 could be an indicator of β-AR blocker efficacy in patients with acute coronary syndrome. Elevated levels of GRK-2 are an early ubiquitous consequence of myocardial injury. In hypertension an increased level of GRK-2 was reported in both animal models and human studies. The role of GRKs in vagally mediated disorders such as vasovagal syncope and atrial fibrillation remains controversial. The role of GRKs in the pathogenesis of neurocardiological diseases provides an insight into the molecular pathogenesis process, opens potential therapeutic options and suggests new directions for scientific research.K Ke ey y w wo or rd ds s: : autonomic, sympathetic, vagal, molecular signaling pathway. Neurocardiovascular pathophysiology: sympathetic versus vagally mediated disordersNeural control of the cardiovascular (CV) system is an integral part of CV physiology and consequently a part of CV pathological mechanisms. Two fundamental parts of the autonomic nervous system -the sympathetic and parasympathetic (vagal) components -play a role in the development and initiation of the pathological process. The classification of neurocardiological disorders by Goldstein [1] is as follows: 1) Sympathetic disorders -diseases in which activation of the catecholamine system worsens an independent pathological state (coronary artery disease, arrhythmias as long QT syndrome, sudden death, heart failure (HF)) as well as diseases in which abnormal catecholaminergic function is etiologic (sympathetic neurocirculatory failure, hypertension, cardiac necrosis and cardiomyopathy), and 2) Vagally mediated disorders -both neurally mediated syncope (vasovagal syncope, carotid sinus hypersensitivity) and vagally mediated atrial fibrillation. Neural regulation of the CV system can be studied by using different techniques [2][3][4][5][6][7][8]. G protein related kinases (GRKs) exist in 7 isoforms -GRK 1-7. They are serine-threonine protein kinases that are C Co or rr re es sp po on nd di in ng g a au ut th ho or r: :

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Role of PI3-Kinase in Isoproterenol and IGF-1 Induced ecNOS Activity

Cited by 37 publications

References 18 publications

Impairment of PI3-K/Akt Pathway Underlies Attenuated Endothelial Function in Aorta of Type 2 Diabetic Mouse Model

Impairment of PI3-K/Akt Pathway Underlies Attenuated Endothelial Function in Aorta of Type 2 Diabetic Mouse Model

Gender Differences in Vascular Reactivity of Aortas from Streptozotocin-Induced Diabetic Mice

State of the art paper The role of G protein coupled receptor kinases in neurocardiovascular pathophysiology

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