Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (AII), acting via its G-protein linked receptor, is an important regulator of cardiac, vascular, and renal function. Following injection of AII into rats, we find that there is also a rapid tyrosine phosphorylation of the major insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) in the heart. This phenomenon appears to involve JAK2 tyrosine kinase, which associates with the AT1 receptor and IRS-1/IRS-2 after AII stimulation. AII-induced phosphorylation leads to binding of phosphatidylinositol 3-kinase (PI 3-kinase) to IRS-1 and IRS-2; however, in contrast to other ligands, AII injection results in an acute inhibition of both basal and insulin-stimulated PI 3-kinase activity. The latter occurs without any reduction in insulin receptor or IRS phosphorylation or in the interaction of the p85 and p110 subunits of PI 3-kinase with each other or with IRS-1/IRS-2. These effects of AII are inhibited by AT1 receptor antagonists. Thus, there is direct cross-talk between insulin and AII signaling pathways at the level of both tyrosine phosphorylation and PI 3-kinase activation. These interactions may play an important role in the association of insulin resistance, hypertension, and cardiovascular disease.
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PMID:Cross-talk between the insulin and angiotensin signaling systems. 890 9

Insulin resistance is associated with both obesity and hypertension. However, the cellular mechanisms of insulin resistance in genetic models of obese-hypertension have not been identified. The objective of the present study was to investigate the effects of genetic obesity on a background of inherited hypertension on initial components of the insulin signal transduction pathway and glucose transport in skeletal muscle and liver. Oral glucose tolerance testing in SHROB demonstrated a sustained postchallenge elevation in plasma glucose at 180 and 240 min compared with lean spontaneously hypertensive rat (SHR) littermates, which is suggestive of glucose intolerance. Fasting plasma insulin levels were elevated 18-fold in SHROB. The rate of insulin-stimulated 3-O-methylglucose transport was reduced 68% in isolated epitrochlearis muscles from the SHROB compared with SHR. Insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrate-1 (IRS-1) in intact skeletal muscle of SHROB was reduced by 36 and 23%, respectively, compared with SHR, due primarily to 32 and 60% decreases in insulin receptor and IRS-1 protein expression, respectively. The amounts of p85 alpha regulatory subunit of phosphatidylinositol-3-kinase and GLUT-4 protein were reduced by 28 and 25% in SHROB muscle compared with SHR. In the liver of SHROB, the effect of insulin on tyrosine phosphorylation of IRS-1 was not changed, but insulin receptor phosphorylation was decreased by 41%, compared with SHR, due to a 30% reduction in insulin receptor levels. Our observations suggest that the leptin receptor mutation fak imposed on a hypertensive background results in extreme hyperinsulinemia, glucose intolerance, and decreased expression of postreceptor insulin signaling proteins in skeletal muscle. Despite these changes, hypertension is not exacerbated in SHROB compared with SHR, suggesting these metabolic abnormalities may not contribute to hypertension in this model of Syndrome X.
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PMID:Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat. 937 89

Trapidil, an antiplatelet drug, has been shown to reduce restenosis after angioplasty. It exerts its action, at least in part, by inhibiting vascular smooth muscle cell proliferation, antagonizing platelet-derived growth factor (PDGF). We examined its site of action on PDGF cellular signaling. Exposure of cultured rat vascular smooth muscle cells to increasing concentrations of trapidil for 18 hours resulted in a dose-dependent reduction in PDGF-BB-stimulated [3H] thymidine incorporation. Trapidil (400 microg/mL) increased PDGF beta-receptor protein by 28+/-8%, whereas PDGF-induced tyrosine phosphorylation of PDGF beta-receptor remained unchanged. PDGF-induced tyrosine phosphorylation of phospholipase Cgamma, the p85 regulatory subunit of phosphatidyl-inositol 3 kinase, Ras GTPase-activating protein, and an adaptor molecule Shc were also not altered. On the other hand, trapidil inhibited PDGF-stimulated mitogen-activated protein kinase (MAP kinase) activity by 35+/-7% at 10 minutes and by 32+/-10% at 6 hours. Activation of Raf-1, an upstream activator of MAP kinase, by PDGF was also attenuated by trapidil. Moreover, protein content of MAP kinase phosphatase-1, which inactivates MAP kinase, was elevated in trapidil-treated cells. These actions of trapidil may be mediated by cAMP. Thus, there was a 1.9-fold increase in cellular cAMP generation in trapidil-treated cells. The present results demonstrate that trapidil antagonizes PDGF-induced mitogenesis and MAP kinase activation in vascular smooth muscle cells, probably through cAMP.
Hypertension 1998 Feb
PMID:Trapidil inhibits platelet-derived growth factor-stimulated mitogen-activated protein kinase cascade. 946 Dec 38

Insulin resistance and hypertension commonly occur together. Pharmacological inhibition of the renin-angiotensin system has been found to reduce not only hypertension, but also insulin resistance. This raises the possibility that the renin-angiotensin system may interact with insulin signalling. We have investigated the relationship between insulin and angiotensin II (AII) intracellular signalling in vivo using an intact rat heart model, and in vitro using rat aorta smooth muscle cells (RASMC). Results generated in the in vivo studies indicate that, like insulin, AII stimulates tyrosine phosphorylation of the insulin receptor substrates IRS-1 and IRS-2. This leads to binding of IRS-1 and IRS-2 to PI3-kinase. However, in contrast to the effect of insulin. IRS-1- and IRS-2-associated PI3-kinase activity is inhibited by AII in a dose-dependent manner. Moreover, AII inhibits insulin-stimulated IRS-1/IRS-2-associated PI3-kinase activity. The in vivo effects of AII are mediated via the AT1 receptor. The results of the in vitro studies indicate that AII inhibits insulin-stimulated, IRS-1-associated PI3-kinase activity by interfering with the docking of IRS-1 with the p85 regulatory subunit of PI3-kinase. It appears that AII achieves this effect by stimulating serine phosphorylation of the insulin receptor beta-subunit IRS-1, and the p85 regulatory subunit of PI3-kinase. These actions result in the inhibition of normal interactions between the insulin signalling pathway components. Thus, we believe that AII negatively modulates insulin signalling by stimulating multiple serine phosphorylation events in the early components of the insulin signalling cascade. Overactivity of the renin-angiotensin system is likely to impair insulin signalling and contribute to insulin resistance observed in essential hypertension.
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PMID:Crosstalk between insulin and angiotensin II signalling systems. 1032 50

Troglitazone, a thiazolizidinedione, has recently been reported to possess anti-arteriosclerotic properties. To evaluate mechanisms underlying the anti-arteriosclerotic effects of troglitazone, we examined the effect of troglitazone on growth, expression of growth factors, and insulin signaling in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) which produce angiotensin II (Ang II) in a homogeneous culture. Troglitazone inhibited basal and serum-stimulated DNA synthesis and inhibited increases in the number of VSMC from SHR and normotensive Wistar-Kyoto (WKY) rats. Its inhibition was greater in VSMC from SHR. Troglitazone abolished DNA synthesis in response to Ang II in VSMC from both rat strains and markedly inhibited DNA synthesis in response to epidermal growth factor (EGF) and platelet-derived growth factor (PDGF)-AA in VSMC from SHR. Troglitazone did not alter the expression of transforming growth factor (TGF)-beta1, PDGF A-chain, or basic fibroblast growth factor (bFGF) mRNAs in VSMC from WKY rats, but it markedly decreased expression of these growth factor mRNAs in VSMC from SHR. Troglitazone markedly decreased basal and Ang II-stimulated expression of extracellular signal-regulated kinase proteins in VSMC from both rat strains. Troglitazone abolished Ang II-induced suppression of phosphatidilinositol 3-kinase (PI3-kinase) activity, insulin receptor substrate-1 (IRS-1) associated tyrosine phosphorylation, and IRS-1 associated p85 levels in VSMC from WKY rats. Basal PI3-kinase activity, tyrosine phosphorylation of IRS-1, and IRS-1 associated p85 levels were lower in VSMC from SHR than in cells from WKY rats. Troglitazone significantly increased PI3-kinase activity, IRS-1 associated tyrosine phosphorylation, and IRS-1 associated p85 levels in VSMC from SHR. These results indicate that troglitazone produce its anti-arteriosclerotic effects through suppression of the action of growth-promoting factors including Ang II, and that troglitazone inhibits Ang II-induced suppression of insulin signaling in VSMC from SHR, suggesting that tissue Ang II may lead to insulin resistance and to arteriosclerosis in hypertension. Troglitazone may be useful in the treatment of insulin resistance as well as of hypertensive vascular diseases.
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PMID:Troglitazone inhibits growth and improves insulin signaling by suppression of angiotensin II action in vascular smooth muscle cells from spontaneously hypertensive rats. 1205 69

Angiotensin II has been shown to contribute to the pathogenesis of insulin resistance; however, the mechanism is not well understood. The present study was undertaken to investigate the potential effect of an angiotensin II type-1 (AT1) receptor blocker, valsartan, to improve insulin resistance and to explore the signaling basis of cross-talk of the AT1 receptor- and insulin-mediated signaling in type 2 diabetic KK-Ay mice. Treatment of KK-Ay mice with valsartan at a dose of 1 mg/kg per day, which did not influence systolic blood pressure, significantly increased insulin-mediated 2-[3H]deoxy-d-glucose (2-[3H]DG) uptake into skeletal muscle and attenuated the increase in plasma glucose concentration after a glucose load and plasma concentrations of glucose and insulin. In contrast, insulin-mediated 2-[3H]DG uptake into skeletal muscle was not influenced in AT2 receptor null mice, and an AT2 receptor blocker, PD123319, did not affect 2-[3H]DG uptake and superoxide production in skeletal muscle of KK-Ay mice. Moreover, we observed that valsartan treatment exaggerated the insulin-induced phosphorylation of IRS-1, the association of IRS-1 with the p85 regulatory subunit of phosphoinositide 3 kinase (PI 3-K), PI 3-K activity, and translocation of GLUT4 to the plasma membrane. It also reduced tumor necrosis factor-alpha (TNF-alpha) expression and superoxide production in skeletal muscle of KK-Ay mice. Specific AT1 receptor blockade increases insulin sensitivity and glucose uptake in skeletal muscle of KK-Ay mice via stimulating the insulin signaling cascade and consequent enhancement of GLUT4 translocation to the plasma membrane.
Hypertension 2004 May
PMID:Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice. 1503 62

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 NOx- (NO2-+NO3-)/cGMP production were unchanged, the clonidine-induced and insulin-induced relaxations and NOx-/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 p110gamma 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.
Hypertension 2004 Dec
PMID:Impairment of PI3-K/Akt pathway underlies attenuated endothelial function in aorta of type 2 diabetic mouse model. 1550 17

Essential hypertension is frequently associated with insulin resistance of skeletal muscle glucose transport, with a potential role of angiotensin II in the pathogenesis of both conditions. The male heterozygous TG(mREN2)27 rat harbors the mouse transgene for renin, exhibits local elevations in angiotensin II, and is an excellent model of both hypertension and insulin resistance. The present study was designed to investigate the potential cellular mechanisms for insulin resistance in this hypertensive animal model, including an assessment of elements of the insulin-signaling pathway. Compared with nontransgenic, normotensive Sprague-Dawley control rats, male heterozygous TG(mREN2)27 rats displayed elevated (P < 0.05) fasting plasma insulin (74%), an exaggerated insulin response (108%) during an oral glucose tolerance test, and reduced whole body insulin sensitivity. TG(mREN2)27 rats also exhibited decreased insulin-mediated glucose transport and glycogen synthase activation in both the type IIb epitrochlearis (30 and 46%) and type I soleus (22 and 64%) muscles. Importantly, there were significant reductions (approximately 30-50%) in insulin stimulation of tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrate-1 (IRS-1), IRS-1 associated with the p85 subunit of phosphatidylinositol 3-kinase, Akt Ser473 phosphorylation, and Ser9 phosphorylation of glycogen synthase kinase-3beta in epitrochlearis and soleus muscles of TG(mREN2)27 rats. Soleus muscle triglyceride concentration was 25% greater in the transgenic group compared with nontransgenic animals. Collectively, these data provide the first evidence that the insulin resistance of the hypertensive male heterozygous TG(mREN2)27 rat can be attributed to specific defects in the insulin-signaling pathway in skeletal muscle.
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PMID:Defective insulin signaling in skeletal muscle of the hypertensive TG(mREN2)27 rat. 1565 91

Existing evidence led us to hypothesize that increases in p85alpha, a regulatory subunit of PI3-kinase, in presympathetic brain areas contribute to hypertension. PI3-kinase p85alpha, p110alpha, and p110delta mRNA was 1.5- to 2-fold higher in the paraventricular nucleus (PVN) of spontaneously hypertensive rats (SHR) compared with their controls, Wistar Kyoto rats (WKY). The increase in p85alpha/p110delta was attenuated in SHR treated with captopril, an angiotensin (Ang)-converting enzyme inhibitor, from in utero to 6 months of age. In the rostral ventrolateral medulla (RVLM), p110delta mRNA was approximately 2-fold higher in SHR than in WKY. Moreover, the increases in mRNA were associated with higher PI3-kinase activity in both nuclei. The functional relevance was studied in neuronal cultures because SHR neurons reflect the augmented p85alpha mRNA and PI3-kinase activity. Expression of a p85 dominant-negative mutant decreased norepinephrine (NE) transporter mRNA and [3H]NE uptake by approximately 60% selectively in SHR neurons. In summary, increased p85alpha/p110delta expression in the PVN and RVLM is associated with increased PI3-kinase activity in the SHR. Furthermore, normalized PI3-kinase p85alpha/p110delta expression within the PVN might contribute to the overall effect of captopril, perhaps attributable to a consequent decrease in NE availability.
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PMID:Increased PI3-kinase in presympathetic brain areas of the spontaneously hypertensive rat. 1566 30

Male heterozygous TG(mREN2)27 rats (TGR) overexpress a murine renin transgene, display marked hypertension, and have insulin resistance of skeletal muscle glucose transport and insulin signaling. We have shown previously that voluntary exercise training by TGR improves insulin-mediated skeletal muscle glucose transport (Kinnick TR, Youngblood EB, O'Keefe MP, Saengsirisuwan V, Teachey MK, and Henriksen EJ. J Appl Physiol 93: 805-812, 2002). The present study evaluated whether this training-induced enhancement of muscle glucose transport is associated with upregulation of critical insulin signaling elements, including insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase, Akt, and glycogen synthase kinase-3. TGR remained sedentary or ran spontaneously in activity wheels for 6 wk, averaging 7.1 +/- 0.8 km/day by the end of week 3 and 4.3 +/- 0.5 km/day over the final week of training. Exercise training reduced total abdominal fat by 20% (P < 0.05) in TGR runners (2.64 +/- 0.01% of body weight) compared with sedentary TGR controls (3.28 +/- 0.01%). Insulin-stimulated (2 mU/ml) glucose transport activity in soleus muscle was 36% greater in TGR runners compared with sedentary TGR controls. However, the protein expression and functionality of tyrosine phosphorylation of insulin receptor and IRS-1, IRS-1 associated with the p85 regulatory subunit of phosphatidylinositol 3-kinase, and Ser473 phosphorylation of Akt were not altered by exercise training. Only insulin-stimulated glycogen synthase kinase-3beta Ser9 phosphorylation was increased (22%) by exercise training. These results indicate that voluntary exercise training in TGR can enhance insulin-mediated glucose transport in skeletal muscle, as well as reduce total abdominal fat mass. However, this adaptive response in muscle occurs independently of modifications in the proximal elements of the insulin signaling cascade.
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PMID:Voluntary exercise training enhances glucose transport but not insulin signaling capacity in muscle of hypertensive TG(mREN2)27 rats. 1571 10


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