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)

Selective peroxisome proliferator-activated receptor (PPAR) gamma modulation is a new pharmacological approach that, based on selective receptor-cofactor interactions and target gene regulation, should result in potent insulin sensitization in the absence of PPARgamma-mediated adverse effects. Here, we characterize two angiotensin receptor blockers (ARBs), telmisartan and irbesartan, as new selective PPAR modulators (SPPARMs). Analysis of PPARgamma protein conformation using protease protection showed that telmisartan directly interacts with the receptor, producing a distinct conformational change compared with a glitazone. Glutathione S-transferase pull-down and fluorescence resonance energy transfer assays revealed selective cofactor binding by the ARBs compared with glitazones with an attenuated release of the nuclear receptor corepressor and absence of transcriptional intermediary factor 2 recruitment by ARBs. Consistently, selective cofactor binding resulted in differential gene expression profiles in adipocytes (ARB versus glitazone treated) assessed by oligo microarray analysis. Finally, telmisartan improved insulin sensitivity in diet-induced obese mice in the absence of weight gain. The present study identifies two ARBs as new SPPARMs. SPPARM activity by ARBs could retain the metabolic efficacy of PPARgamma activation with reduction in adverse effects exerting in parallel AT1 receptor blockade. This may provide a new therapeutic option for better cardiovascular risk management in metabolic diseases and may initiate the development of new classes of drugs combining potent antihypertensive and antidiabetic actions.
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PMID:Molecular characterization of new selective peroxisome proliferator-activated receptor gamma modulators with angiotensin receptor blocking activity. 1630 60

Telmisartan (Micardis, Pritor), a highly selective angiotensin II (AII) type 1 (AT1) receptor antagonist, is approved for the treatment of hypertension, either as monotherapy or in combination with other antihypertensive agents. The long elimination half-life of telmisartan ensures the drug provides effective reductions in blood pressure (BP) across the entire 24-hour dosage interval. Extensive evidence from well designed clinical trials and the clinical practice setting indicates that telmisartan, either as monotherapy or in combination with other antihypertensive agents, provides long-term antihypertensive efficacy and is well tolerated in a broad spectrum of hypertensive patients, including the elderly and those with coexisting type 2 diabetes mellitus, metabolic syndrome and/or renal impairment. Notably, BP control is sustained throughout the 24-hour dosage interval, including during the last 6 hours of this period. Independent of its effect on BP, telmisartan displays favourable effects on insulin resistance, lipid levels, left ventricular hypertrophy (LVH) and renal function. The consistent antihypertensive efficacy during the entire 24-hour dosage interval and sustained BP-lowering effect in the long term, combined with its favourable tolerability profile, mean that telmisartan is a valuable first-line treatment option for the management of essential hypertension.
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PMID:Telmisartan: a review of its use in the management of hypertension. 1639 68

The apelin receptor was initially classed as an orphan G-protein-coupled receptor, and little was known about its physiological functions until apelin, the endogenous ligand, was identified. Similarities between the structure and anatomical distribution of apelin and its receptor and that of angiotensin II and the angiotensin AT1 receptor provide clues about the physiological functions of this novel signal-transduction system. Now, roles have been established for the apelin system in lowering blood pressure, as a potent cardiac inotrope, in modulating pituitary hormone release and food and water intake, in stress activation, and as a novel adipokine that is excreted from fat cells and regulates insulin. Given its broad array of physiological roles, apelin has attracted much interest as a target for novel therapeutic research and drug design.
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PMID:Unravelling the roles of the apelin system: prospective therapeutic applications in heart failure and obesity. 1653 Aug 55

Current evidence points to renin-angiotensin system as a key mediator in ischemia-reperfusion injury. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand, has recently been shown to confer cardioprotection against ischemia-reperfusion in animal models. We sought to examine the expression of ANG II receptors during PPAR-gamma-mediated cardioprotection. Male Sprague-Dawley rats (nondiabetic) were fed either regular rat chow (control diet group, n = 9) or rosiglitazone-rich diet (rosiglitazone-rich diet group, n = 9) and were subjected to 1 h of myocardial ischemia followed by 1 h of reperfusion. A third group of rats had only thoracotomy and pericardiotomy and served as a sham control group (n = 9). Hemodynamics, infarct size, and expression of ANG II type 1 and type 2 receptors (AT1 and AT2) were measured in all groups. There was a 58% reduction of infarct size in the rosiglitazone-rich diet group (P < 0.01 vs. control diet group). Increased myocardial expression of AT(1) receptors in the ischemic-reperfused myocardium was attenuated in the rosiglitazone-rich diet group (P < 0.05 vs. control diet group). Importantly, myocardial AT2 mRNA and protein expression were significantly increased (by >100-fold) in the rosiglitazone-rich diet group (P < 0.05). These changes were accompanied by inhibition of p42/44 MAPK in the rosiglitazone-rich diet group, while the Akt1 expression, believed to mediate insulin sensitization, remained similar in all three groups. The cardioprotective effects of rosiglitazone against myocardial ischemia-reperfusion injury are independent of its insulin-sensitizing properties and are associated with significant overexpression of AT2 receptors along with inhibition of p42/44 MAPK.
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PMID:Cardioprotective effects of rosiglitazone are associated with selective overexpression of type 2 angiotensin receptors and inhibition of p42/44 MAPK. 1658 19

AT1 receptor blockers and ACE inhibitors decrease the risk for new onset diabetes mellitus. The phenomenon could be related to a direct angiotensin II effect on tissue metabolism. To address the issue, we recruited eighteen obese hypertensive patients. Patients were randomized to double-blind treatment with either valsartan (n = 8) or atenolol (n = 10) for thirteen weeks. They underwent an oral glucose tolerance test before and during active treatment, while metabolism was monitored through subcutaneous and intramuscular microdialysis and indirect calorimetry. After glucose ingestion, venous glucose and insulin concentrations increased rapidly while systemic free fatty acid concentrations were suppressed. Dialysate glucose and lactate concentrations increased briskly in adipose tissue and in skeletal muscle. Dialysate glycerol decreased profoundly in both tissues. Respiratory quotient increased markedly after glucose ingestion. These responses were identical at baseline and during active treatment either drug. We conclude that AT1 receptor blockade in obese hypertensive patients has no effect on interstitial glucose supply, lipolysis, and substrate oxidation. One possible explanation is that angiotensin II levels in obese hypertensives are not sufficient to elicit the metabolic changes that have been observed after direct angiotensin II application. The exact mechanism by which inhibition of the renin-angiotensin-aldosterone system decreases the diabetes risk remains unresolved and requires further study.
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PMID:The effect of oral glucose loads on tissue metabolism during angiotensin II receptor and beta-receptor blockade in obese hypertensive subjects. 1671 29

Angiotensin II antagonists (AIIAs) were introduced to treat hypertension about 10 years ago. During this period they were evaluated not only in terms of efficacy and safety but also in several large studies with clinical outcomes. They are efficacious in all clinical forms of hypertension and are effective also in all ethnic groups. Cardiovascular and renal protection in proteinuric diabetic nephropathy beyond blood pressure reduction was proved in major clinical studies: Losartan Intervention For Endpoint reduction in hypertension study (LIFE), Reduction of Endpoint in Non-Insulin dependent Diabetes Mellitus with the AII Antagonist Losartan (RENAAL) and Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT). Their blood pressure independent protective effect is also mentioned by the blockade of AT1 receptor. As a class AIIs have a tolerability profile similar to placebo.
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PMID:Angiotensin II antagonists: clinical experience in the treatment of hypertension, prevention of cardiovascular outcomes and renal protection in diabetic nephropathy and proteinuria. 1676 99

This study investigates the mechanisms whereby angiotensin II (Ang II) signaling contributes to cell growth and glucose metabolism in cultured vascular smooth muscle cells (VSMCs) from male Wistar fatty rats (WF) and their littermates (Wistar lean rats, WL). The levels of the medial outgrowth rate of VSMCs and Ang II type-1 receptors (AT1R) in aortae from WF were more enhanced than those in aortae from WL, but the level of Ang II type-2 receptors (AT2R) was not different. A mixture of insulin and Ang II additively increased the values of [(3)H]-thymidine incorporation in WF and WL, which was inhibited by olmesartan, an AT1 receptor blockade (ARB), but not by PD123,319, an AT2 receptor blockade. Similarly, insulin and Ang II phosphorylated extracellular-regulated protein kinase 1/2, retinoblastoma tumor suppressor protein, and cyclic AMP response element binding protein, and these levels were higher in WF than in WL. In contrast, the phosphorylation was suppressed by olmesartan but not PD123,319. Insulin-stimulated Akt phosphorylation and 2-deoxy-d-glucose uptake in WF were significantly reduced by Ang II, and the reduction was ameliorated by olmesartan but not PD123,319. Differently from the result of Akt, the phosphorylation of the insulin-stimulated insulin receptor beta-subunit was not affected by Ang II, olmesartan, or PD123,319. However, the phosphorylation of insulin-stimulated insulin-related substrate (IRS)-1 was suppressed by Ang II, and the suppression was ameliorated by olmesartan, but not PD123,319, in both WF and WL. In contrast, the phosphorylation of IRS-1 on Ser(307) was elevated by the Ang II, and the elevation was suppressed by olmesartan, but not by PD123,319, in both WF and WL. These findings demonstrated that Ang II signaling contributes to cell proliferation and inhibition of the insulin signaling pathways through AT1R, but not trough AT2R, in both non-diabetic and diabetic VSMCs.
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PMID:Role of angiotensin II type-1 and type-2 receptors on vascular smooth muscle cell growth and glucose metabolism in diabetic rats. 1693 5

In this issue of Cell Metabolism, Semenkovich and his colleagues show that ATM, a protein well known for its roles in the cellular response to DNA breaks, may also be linked to metabolic and cardiovascular diseases (Schneider et al., 2006). ATM seemingly does this by inhibiting JNK, a stress kinase involved in inflammation with related effects in insulin resistance and atherosclerosis. In an interesting twist, the authors show that chloroquine, an antimalarial drug, also activates ATM, which inhibits JNK, and improves insulin sensitivity and cardiovascular effects. These findings provide potential new insights into the pathogenesis and treatment of metabolic syndrome.
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PMID:Banking on ATM as a new target in metabolic syndrome. 1708 11

Metabolic syndrome is associated with insulin resistance and atherosclerosis. Here, we show that deficiency of one or two alleles of ATM, the protein mutated in the cancer-prone disease ataxia telangiectasia, worsens features of the metabolic syndrome, increases insulin resistance, and accelerates atherosclerosis in apoE-/- mice. Transplantation with ATM-/- as compared to ATM+/+ bone marrow increased vascular disease. Jun N-terminal kinase (JNK) activity was increased in ATM-deficient cells. Treatment of ATM+/+apoE-/- mice with low-dose chloroquine, an ATM activator, decreased atherosclerosis. In an ATM-dependent manner, chloroquine decreased macrophage JNK activity, decreased macrophage lipoprotein lipase activity (a proatherogenic consequence of JNK activation), decreased blood pressure, and improved glucose tolerance. Chloroquine also improved metabolic abnormalities in ob/ob and db/db mice. These results suggest that ATM-dependent stress pathways mediate susceptibility to the metabolic syndrome and that chloroquine or related agents promoting ATM activity could modulate insulin resistance and decrease vascular disease.
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PMID:ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome. 1708 7

Hypertension is often associated with an impairment of glucose tolerance and is a risk factor for the development of type 2 diabetes mellitus. The occurrence of diabetes may be also influenced by the selection of the type of antihypertensive treatment. While it has been shown that the use of older type antihypertensives - diuretics and beta-blockers - may precipitate diabetes, newer drugs which inhibit the renin-angiotensin system have a positive effect on glucose tolerance. Several recent clinical trials of ACE-inhibitors and AT1-blockers have demonstrated a decreased risk of the occurrence of diabetes in comparison with placebo or conventional antihypertensive drugs. The mechanisms responsible for the antidiabetic effect of these newer antihypertensive agents remain largely speculative. Insulin resistance may be improved in several ways, e.g. by changes in microcirculation or direct effects on insulin response and glucose transport in target organ cells. However, as shown in experimental studies, improved islet function and insulin secretion may also have role due to an inhibitory effect on the local renin-angiotensin system in the pancreas. Ongoing prospective clinical trials having the occurrence of diabetes as a primary specified endpoint should confirm the preventive potential of the inhibitors of the renin-angiotensin system. Since direct comparisons are lacking, current data are inconclusive as to the superiority of one of the two classes of these inhibitors or of any single drug. Nevertheless, inhibitors of the renin-angiotensin system should definitely represent first choice antihypertensive agents for persons with additional risk factors such as family history of diabetes, obesity or impaired glucose tolerance.
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PMID:[Prevention of type 2 diabetes mellitus due to antihypertensive treatment affecting renin-angiotensin system]. 1709 2


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