Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0004135 (ATM)
13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-like growth factor (IGF)-1 inhibits apoptosis, but its mechanism is unknown. Myocyte stretching activates p53 and p53-dependent genes, leading to the formation of angiotensin II (Ang II) and apoptosis. Therefore, this in vitro system was used to determine whether IGF-1 interfered with p53 function and the local renin-angiotensin system (RAS), decreasing stretch-induced cell death. A single dose of 200 ng/ml IGF-1 at the time of stretching decreased myocyte apoptosis 43% and 61% at 6 and 20 hours. Ang II concentration was reduced 52% at 20 hours. Additionally, p53 DNA binding to angiotensinogen (Aogen), AT1 receptor, and Bax was markedly down-regulated by IGF-1 via the induction of Mdm2 and the formation of Mdm2-p53 complexes. Concurrently, the quantity of p53, Aogen, renin, AT1 receptor, and Bax was reduced in stretched myocytes exposed to IGF-1. Conversely, Bcl-2 and the Bcl-2-to-Bax protein ratio increased. The effects of IGF-1 on cell death, Ang II synthesis, and Bax protein were the consequence of Mdm2-induced down-regulation of p53 function. In conclusion, the anti-apoptotic impact of IGF-1 on stretched myocytes was mediated by its capacity to depress p53 transcriptional activity, which limited Ang II formation and attenuated the susceptibility of myocytes to trigger their endogenous cell death pathway.
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PMID:Insulin-like growth factor-1 induces Mdm2 and down-regulates p53, attenuating the myocyte renin-angiotensin system and stretch-mediated apoptosis. 1002 14

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

Evidence exists for the presence of a discrete tissue renin-angiotensin system (RAS) in mouse and rat pancreas that is thought largely to be associated with the vasculature. To investigate this in the human pancreas, and to establish whether the cellular sites of RAS components include the islets of Langerhans, we used immunocytochemistry to localise the expression of angiotensin II (AT1) receptors and (pro)renin, and non-isotopic in situ hybridisation to localise transcription of the (pro)renin gene. Identification of cell types in the islets of Langerhans was achieved using antibodies to glucagon and insulin. The results show the presence of the AT1 receptor and (pro)renin both in the beta cells of the islets of Langerhans, and in endothelial cells of the pancreatic vasculature. Transcription of (pro)renin mRNA, however, was confined to connective tissue surrounding the blood vessels and in reticular fibres within the islets. These findings are similar to those obtained in other tissues, and suggest that renin may be released from its sites of synthesis and taken up by possible cellular sites of action. The results presented here suggest that a tissue RAS may be present in human pancreas and that it may directly affect beta cell function as well as pancreatic blood flow.
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PMID:The tissue renin-angiotensin system in human pancreas. 1032 Aug 30

Angiotensin II antagonists block the actions of angiotensin II by occupying the AT1 receptors. With this blockade there is no bradykinin increase, the angiotensin II synthetized by the cardiac chymase is also blocked, and the AT2 receptor is stimulated (antiproliferative effect). In animal experiments, losartan reverses left ventricular hypertrophy, inhibits myocardial fibrosis and diabetic glomerulosclerosis and significantly protects from vascular cerebral diseases. In humans, the efficacy of the angiotensin II antagonists and that of other antihypertensives is similar and is potentiated by the addition of a thiazide. They are very well tolerated and no important adverse reactions are reported. Losartan decreases insulin resistance, has a very favourable hemodynamic and neurohormonal profile in patients with cardiac insuficiency, reverses proteinuria and has a uricosuric effect. Angiotensin II antagonists are a step forward towards the ideal antihypertensive drugs.
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PMID:[Therapy of arterial hypertension with angiotensin receptor blockers]. 1037 49

Insulin responsiveness was studied in isolated adipocytes from the normotensive Wistar Kyoto (WKY) rat and the spontaneously hypertensive rat (SHR). The effect of insulin (0.1 to 5 nmol/L) on glucose uptake (glucose transport and lipogenesis) was measured, and the maximal effect of insulin (Emax) and the dose of insulin required to elicit 50% of the maximal response (EC50) were calculated. A diminished Emax on lipogenesis without changes in the EC50 was detected in SHRs. The Emax was 0.49 +/- 0.09 (SHR) and 1.16 +/- 0.14 (WKY) micromol/10(5) cells (P < .05), and the EC50 was 0.13 +/- 0.03 and 0.11 +/- 0.02 nmol/L for WKY and SHR, respectively. Similar results were obtained when measuring insulin-stimulated glucose transport. A 30-day long-term treatment with enalapril (20 mg/kg/d) normalized insulin responsiveness in adipocytes from SHRs. The effect of enalapril was suppressed when SHRs were pretreated with enalapril and 150 microg/kg/d of the bradykinin (BK) B2-receptor blocker Hoe 140. Pretreatment with losartan (40 mg/kg/d) did not improve insulin action in the SHR. Since these results were obtained with isolated cells in which glucose availability was not a function of blood flow, and the effect of insulin in the SHR was improved by pretreatment with an angiotensin-converting enzyme (ACE) inhibitor but not with the AT1-receptor blocker, it appears that the insulin resistance linked to the hypertension is not related to changes in blood flow.
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PMID:Insulin resistance in adipocytes from spontaneously hypertensive rats: effect of long-term treatment with enalapril and losartan. 1045 71

Although angiotensin AT1 receptor antagonist(AT1 A) improves insulin sensitivity in insulin resistant models, its effect on spontaneously hypertensive rats(SHR) has not been elucidated. We investigated the effects of AT1 A, candesartan on insulin sensitivity in SHR/Izm and the role of sympathetic activity in its mechanism. In 9-week-old SHR/Izm, candesartan(10 mg/kg/day) was given orally for 5 days. A control group received vehicle. On the 6th day, mean arterial pressure (MAP), heart rate(HR), plasma norepinephrine (PNE), plasma epinephrine(PE) and plasma dopaminc(PDA) were measured in both groups (n = 11 in each group). In the separate groups of rats, fasting blood glucose (FBG), serum sodium, serum potassium and insulin sensitivity by steady state blood glucose (SSBG) were assessed (n = 16 in the Candesartan group and n = 8 in the Control group). MAP and SSBG were significantly lower in the Candesartan group (117 +/- 2 mmHg and 138 +/- 5 mg/dl) than those in the Control group(155 +/- 6 mmHg and 164 +/- 10 mg/dl). Body weight, HR, FBG, PNE, PE, PDA, sodium and potassium were the same between the groups. In conclusion, since AT1 A, candesartal lowers blood pressure and improves insulin sensitivity irrespective of sympathetic activity in SHR/Izm, it is useful in treating hypertension associated with insulin resistance.
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PMID:[Effects of angiotensin II receptor antagonist on insulin sensitivity and sympathetic activity in spontaneously hypertensive rats]. 1057 94

Some patients with certain preexisting health conditions may be at elevated risk for unusually intense radiation-induced skin reactions and late tissue damage from high-dose interventional procedures. The authors present a case report of a patient with mixed connective tissue disease and non-insulin-dependent diabetes mellitus who developed an unusual complication after placement of a transjugular intrahepatic portosystemic shunt. On the basis of a review of the literature, the following experiences may help identify patients at increased risk: previous high-dose procedures, connective tissue disease, diabetes mellitus, and homozygosity for ataxia telangiectasia.
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PMID:Severe skin reactions from interventional fluoroscopy: case report and review of the literature. 1058 Sep 52

The aim of the present study was to investigate the proliferative effects of Ang II in human cardiac fibroblasts. The effects of Ang II in human cardiac fibroblasts on the 3H-thymidine incorporation, the cell number, the 3H-leucine incorporation and the total protein content were measured. The expression of receptor mRNA was performed by reverse transcription-polymerase chain reaction (RT-PCR). Ang II increased 3H-leucine incorporation in a concentration-dependent manner but not 3H-thymidine incorporation in primary cultures of human cardiac fibroblasts. The maximum effect (24 +/- 3% over control) was obtained at a concentration of 10 nM. There were no significant alterations of cell number or total protein content, suggesting that Ang II stimulated protein synthesis but did not induce hypertrophy. The accumulation of 3H-leucine was blocked by the AT1 receptor antagonist candesartan but not by the AT2 receptor antagonist PD123319. By using RT-PCR, both AT1 and AT2 receptors mRNA were found to be expressed in human cardiac fibroblasts. The selective MAPKK inhibitor PD098059, the protein kinase C inhibitor K252a or the phospholipase C inhibitor U73122 did not significantly inhibit Ang II augmented 3H-leucine incorporation. However, this was significantly blocked by the Ca2+-dependent protein kinase C inhibitor GO6976, the non-selective protein kinase inhibitor staurosporine and the tyrosine kinase inhibitor tyrphostin 25. The effects of Ang II were unaffected by the Gi-protein blocker pertussis toxin, indicating a Gi-protein-independent pathway. Ang II was synergistic with insulin but showed no significant increase on 3H-leucine incorporation when combined with PDGF or EGF. In summary, Ang II stimulates protein synthesis through AT1 receptors in human cardiac fibroblasts, but has no hypertrophic or hyperplastic effect. The response is mediated by a MAPKK-independent and Ca2+-sensitive PKC-dependent pathway.
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PMID:Angiotensin II type 1 receptors stimulate protein synthesis in human cardiac fibroblasts via a Ca2+-sensitive PKC-dependent tyrosine kinase pathway. 1071 68

Epidemiological evidence suggests that reducing blood pressure alone in hypertensive patients delays the onset of cardiovascular events without necessarily preventing the progression of chronic target-organ disease, such as end-stage renal failure and heart failure. Successful clinical management of hypertensive patients will therefore not be possible unless therapies are aimed both at the effective control of blood pressure and at the preservation of target-organ function. The new angiotensin II type I (AT1) receptor blocker candesartan cilexetil has been shown to be effective in reducing target-organ damage in animal models of hypertension, even at doses that do not produce significant reductions in blood pressure. Protective effects of candesartan cilexetil towards the heart and kidney have also been demonstrated in the clinical studies that have been conducted to date. Thus, candesartan cilexetil has been shown to induce regression of left ventricular hypertrophy within 8-12 weeks of treatment and to improve renal haemodynamics, both acutely and after 6 weeks of treatment in hypertensive patients. Furthermore, in hypertensive patients with co-existent non-insulin-dependent diabetes mellitus and microalbuminuria, 12 weeks of treatment with candesartan cilexetil, 8-16 mg, significantly reduced urinary albumin excretion. Clinical evidence is therefore accumulating that the antihypertensive efficacy and tolerability profile already established for candesartan cilexetil is combined with the renal and cardioprotective effects necessary for optimal management of hypertension.
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PMID:Preserving target-organ function with candesartan cilexetil in patients with hypertension. 1105 35

Serum levels of insulin and insulin-like growth factors and their binding proteins (IGFs and IGFBPs, respectively) are changed in human neurodegenerative diseases of very different etiology, such as Alzheimer's disease, amyotrophic lateral sclerosis, or cerebellar ataxia. However, the significance of these endocrine disturbances is not clear. We now report that in two very different inherited neurodegenerative conditions, ataxia-telangiectasia (AT) and Charcot-Marie-Tooth 1A (CMT-1A) disease, serum levels of IGFs are also altered. Both types of patients have increased serum IGF-I and IGFBP-2 levels, and decreased serum IGFBP-1 levels, while only AT patients have high serum insulin levels. Furthermore, serum IGFs are also changed in three different animal models of neurodegeneration: neurotoxin-induced motor discoordination, diabetic neuropathy, and hereditary cerebellar ataxia. In these three models, serum insulin levels are significantly decreased, serum IGF-I and IGFBP-1, -2, and -3 are decreased in diabetic and neurotoxin-injected rats, while serum IGFBP-1 is increased in hereditary ataxic rats. Altogether, these observations indicate that a great variety of neurodegenerative diseases show endocrine perturbations, resulting in changes in serum IGFs levels. These perturbations are disease-specific and are probably due to metabolic and endocrine derangements, nerve cell death, and sickness-related disturbances associated to the neurodegenerative process. Our observations strongly support the need to evaluate serum IGFs in other neurodegenerative conditions.
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PMID:Neurodegeneration is associated to changes in serum insulin-like growth factors. 1111 63


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