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)

Activation of the renin-angiotensin-aldosterone system plays an important role in the pathogenesis of endothelial dysfunction and atherosclerosis. Studies evaluating the effect of AT1-receptor blockers on endothelial dysfunction in patients with coronary artery disease (CAD) revealed mixed results. Studies addressing the effects of AT1-receptor blockers on the coronary and peripheral function in the same study population, are still lacking. We therefore aimed to test the effects of long-term therapy with the AT1-receptor blocker irbesartan (IRB) on both, the coronary and peripheral endothelial function in patients with CAD. Seventy-two patients with CAD were randomly assigned to double-blinded treatment for 6 months with IRB 300 mg per day or placebo, respectively. Coronary and peripheral endothelial function were measured by intracoronary infusion of acetylcholine (final intracoronary concentration 10(-7.3) to 10(-5.6)M) and by determining flow-dependent dilation (FMD) of the brachial artery, respectively. IRB significantly improved FMD, while no change of coronary endothelial function was observed. Interestingly, plasma levels of N(G),N(G)-dimethyl-arginine, and the isoprostane excretion rate were not modified. IRB treatment improves peripheral but not coronary endothelial dysfunction in patients with CAD. Since reduced FMD of the brachial artery has been shown to be associated with a high-cardiovascular event rate, improvement of FMD by IRB may lead to better prognosis of patients with CAD.
Atherosclerosis 2007 Oct
PMID:AT1-receptor blockade with irbesartan improves peripheral but not coronary endothelial dysfunction in patients with stable coronary artery disease. 1697 Sep 50

Kinins are synthesized from their precursors by different enzymes and participate in the regulation of cardiovascular function through bradykinin (BK) B1 and B2 receptors. They modulate blood coagulation by exerting antithrombotic and profibrinolytic actions. By activating B2 receptors that results in the release of nitric oxide and prostacyclin, kinins inhibit vascular smooth muscle growth and neointima formation, which may play an inhibitory role on the atherosclerosis development, while through the activation of B1 receptors, they may play a deleterious role in this disease. Kinins are potent endogenous vasodilators that are involved in the regulation of coronary vascular tone. However, due to their metabolic characteristics, these peptides act mainly as an autocrine/paracrine factor to locally regulate blood perfusion of organs. By modulating cellular energy metabolism and myocardial oxygen consumption, they protect cardiac and vascular endothelial function in myocardial ischemia and heart failure. Finally, mounting evidence indicates that kinins are involved in the actions of some drugs actually used in the treatment of cardiovascular diseases such as angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor antagonists. Taken together, the kinin system constitutes a potential therapeutic target for cardiovascular diseases. Experiments in animals attempted to explore the kinin system as a therapeutic means, including the mobilization of endogenous kinins using pharmacological agents, searching BK analogs with long-acting properties and gene therapies. However, the potential values of the kinin system have not been taken into consideration in clinical practice for cardiovascular indications.
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PMID:Kinins and cardiovascular diseases. 1701 36

Accumulation and modification of low density lipoproteins (LDL) within the vessel wall represent key events in atherogenesis. Secretory phospholipase A2 type IIA (sPLA2-IIA) modulates the enzymatic process of LDL-modification and was recently identified as an independent predictor of coronary events in patients with coronary artery disease (CAD). Angiotensin II (ANG II) type 1 (AT1)-receptor blockade reduces LDL-modification and atherosclerotic plaque formation in rodent and primate models of atherosclerosis. Therefore, we assessed whether ANG II via its AT1-receptor enhances sPLA2-IIA-dependent lipid peroxidation in vitro and in patients with CAD. Stimulation of rat aortic smooth muscle cells with ANG II (10(-7) mol/L) enhanced sPLA2-IIA protein expression, activity as well as LDL-peroxidation, determined by western blot, activity assay and malondialdehyde (MDA)-assay and diene formation, respectively, and were blunted by AT1-receptor blockade (Losartan, 10(-5) mol/L). In addition, ANG II-induced sPLA2 activity and LDL-peroxidation were abolished by the sPLA2-IIa activity inhibitor LY311727 (10(-5) mol/L). To evaluate a potential clinical implication, patients (n=18) with angiographically documented CAD were treated with the AT1-receptor blocker Irbesartan (IRB; 300 mg/d) for 12 weeks. Blood samples were obtained from patients pre- and post-treatment and from healthy volunteers. SPLA2-IIA serum level and activity, circulating antibodies against oxidized LDL (oxLDL), oxLDL and MDA were determined in patients and found to be significantly increased compared to healthy volunteers. IRB therapy reduced these markers of inflammation, whereas total cholesterol, HDL- and LDL-fractions remained unchanged. ANG II may elicit pro-atherosclerotic effects via type IIA sPLA2-dependent LDL-modifications. Chronical AT1-receptor blockade reduces sPLA2-IIA level and activity and subsequently lipid peroxidation. Theses findings represent a novel anti-atherosclerotic mechanism and imply that AT1-receptor blockade elicits anti-atherosclerotic potencies even in the absence of plasma cholesterol reduction.
Atherosclerosis 2007 Sep
PMID:Angiotensin II type 1-receptor antagonism prevents type IIA secretory phospholipase A2-dependent lipid peroxidation. 1706 18

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

Increased blood pressure induces functional and structural changes of the vascular endothelium. Depression of endothelium-dependant vasodilatation is an early manifestation of endothelial dysfunction due to hypertension. It can be demonstrated by pharmacological or physiological tests. Decreased availability of nitric oxide (NO) is a major determinant of the depression of vasodilatation. It may be caused by a reduction in the activity of NO-endothelial synthase (NOSe) related to: 1) a deficit in substrate (L-arginine), 2) an inhibition by asymmetrical dimethylarginine, 3) a deficit in the cofactor tetrahydrobiopterin (BH4). However, the increase in oxidative stress, a producer of superoxide radicals which combine with NO to form peroxynitrates (ONOO-), is the determining factor. It is related to activation of membranous NAD(P)H oxidases initiated by the stimulation of activating mecanosensors of protein C kinase. The message is amplified by oxidation of BH4 which transforms the NOSe into a producer of superoxide radicals. A cascade of auto-amplification loops leading to atherosclerosis and its complications is then triggered. The superoxide radicals and the peroxynitrates oxidise the LDL-cholesterol. They activate the nuclear factor-kappaB which controls the genes stimulating the expression of many proteins: angiotensinogen and AT1 receptors which stimulate the sympathetic system, receptors of oxidised LDL, adhesion and migration factors (ICAM-1, VCAM-1, E-selectin and MCP-1), pro-inflammatory cytokins (interleukines and TNF-alpha), growth factors (MAP kinases), plasminogen activator inhibitor 1. The monocytes and smooth muscle cells produce metalloproteinases and pro-inflammatory cytokins which destabilise the atheromatous plaque and favourise vascular remodelling. Inshort, the endothelial dysfunction due to hypertension plays a role in a complex physiopathological process and is a marker of future cardiovascular events.
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PMID:[Hypertension, endothelial dysfunction and cardiovascular risk]. 1710 Jan 43

Endothelial NO synthase (eNOS) is the predominant enzyme responsible for vascular NO synthesis. A functional eNOS transfers electrons from NADPH to its heme center, where L-arginine is oxidized to L-citrulline and NO. Common conditions predisposing to atherosclerosis, such as hypertension, hypercholesterolemia, diabetes mellitus and smoking, are associated with enhanced production of reactive oxygen species (ROS) and reduced amounts of bioactive NO in the vessel wall. NADPH oxidases represent major sources of ROS in cardiovascular pathophysiology. NADPH oxidase-derived superoxide avidly interacts with eNOS-derived NO to form peroxynitrite (ONOO(-)), which oxidizes the essential NOS cofactor (6R-)5,6,7,8-tetrahydrobiopterin (BH(4)). As a consequence, oxygen reduction uncouples from NO synthesis, thereby rendering NOS to a superoxide-producing pro-atherosclerotic enzyme. Supplementation with BH(4) corrects eNOS dysfunction in several animal models and in patients. Administration of high local doses of the antioxidant L-ascorbic acid (vitamin C) improves endothelial function, whereas large-scale clinical trials do not support a strong role for oral vitamin C and/or E in reducing cardiovascular disease. Statins, angiotensin-converting enzyme inhibitors and AT1 receptor blockers have the potential of reducing vascular oxidative stress. Finally, novel approaches are being tested to block pathways leading to oxidative stress (e.g. protein kinase C) or to upregulate antioxidant enzymes.
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PMID:Janus-faced role of endothelial NO synthase in vascular disease: uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal. 1713 97

Angiotensin II (Ang II) plays a key role in the regulation of blood pressure and fluid homeostasis. Valsartan is a highly selective Ang II receptor blocker that specifically and selectively blocks Ang II at the AT1-receptor. In animal models, valsartan has shown positive effects on vasoconstriction, proliferation, remodelling, endothelial function and thrombogenesis, inflammation and atherosclerosis. These data are likely to be confirmed by the results of current clinical trials and valsartan is set to provide improved cardiovascular therapy in the future.
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PMID:New basic science initiatives with the angiotensin II receptor blocker valsartan. 1719 10

Discovery of the unexpected intercellular messenger and transmitter nitric oxide (NO) was the highlight of highly competitive investigations to identify the nature of endothelium-derived relaxing factor. This labile, gaseous molecule plays obligatory roles as one of the most promising physiological regulators in cardiovascular function. Its biological effects include vasodilatation, increased regional blood perfusion, lowering of systemic blood pressure, and antithrombosis and anti-atherosclerosis effects, which counteract the vascular actions of endogenous angiotensin (ANG) II. Interactions of these vasodilator and vasoconstrictor substances in the circulation have been a topic that has drawn the special interest of both cardiovascular researchers and clinicians. Therapeutic agents that inhibit the synthesis and action of ANG II are widely accepted to be essential in treating circulatory and metabolic dysfunctions, including hypertension and diabetes mellitus, and increased availability of NO is one of the most important pharmacological mechanisms underlying their beneficial actions. ANG II provokes vascular actions through various receptor subtypes (AT1, AT2, and AT4), which are differently involved in NO synthesis and actions. ANG II and its derivatives, ANG III, ANG IV, and ANG-(1-7), alter vascular contractility with different mechanisms of action in relation to NO. This review article summarizes information concerning advances in research on interactions between NO and ANG in reference to ANG receptor subtypes, radical oxygen species, particularly superoxide anions, ANG-converting enzyme inhibitors, and ANG receptor blockers in patients with cardiovascular disease, healthy individuals, and experimental animals. Interactions of ANG and endothelium-derived relaxing factor other than NO, such as prostaglandin I2 and endothelium-derived hyperpolarizing factor, are also described.
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PMID:Interaction of endothelial nitric oxide and angiotensin in the circulation. 1732 48

The receptor for advanced glycation end products (RAGE) and the angiotensin II type I receptor (AT1R) have been separately linked to the pathogenesis of diabetic atherosclerosis. However, no prior study has addressed a linkage between RAGE and AT1R in diabetic atherogenesis. Therefore, we tested the hypothesis that upregulation of the ligand-RAGE axis via AT1R is an essential process underlying the disease. Diabetes was induced in apolipoprotein E-deficient (ApoE(-/-)) mice by streptozotocin, and diabetic mice were treated with AT1 receptor blocker (ARB) for 6 weeks. Diabetic ApoE(-/-) mice that were AT1R-deficient (ApoE(-/-)AT1aR(-/-)) were also investigated. In diabetic ApoE(-/-) mice, AT1R was found to increase within 1 week of diabetes induction, before ligand-RAGE pathway activation and other inflammatory changes were observed. Both ARB treatment and AT1aR deficiency suppressed diabetic atherosclerosis, ligand-RAGE expression and inflammatory changes. In contrast, upregulation of the ligand-RAGE pathway was noted in atherosclerotic plaques from non-diabetic ApoE(-/-) mice infused with angiotensin II. In cultured vascular smooth muscle cells, angiotensin II increased RAGE protein levels via AT1R stimulation. Upregulation of the ligand-RAGE pathway via AT1R is an essential mechanism in diabetic atherosclerosis, implying that ARB might decrease diabetic atherogenesis by inhibiting ligand-RAGE signals.
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PMID:Upregulation of the ligand-RAGE pathway via the angiotensin II type I receptor is essential in the pathogenesis of diabetic atherosclerosis. 1776 Nov 93


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