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)

Activated matrix metalloproteinases (MMPs) in patients with acute coronary syndromes may contribute to plaque destabilization. Since reactive oxygen species (ROS) induce MMP-2 and angiotensin II (ANG II) enhances NADPH-oxidase-dependent ROS formation, we assessed whether ANG II induces MMP-2 in a NADPH-oxidase-dependent manner. MMP-2 mRNA expression and activity were analyzed in wildtype and p47phox-deficient (p47phox-/-) murine smooth muscle cells (SMC). To address a clinical implication, sections of human atherosclerotic arteries were stained for MMP-2, p47phox, ANG II, AT1-receptor, and alpha-smooth muscle cell actin (alpha-SMC actin). MMP-2 protein expression and activity from these arteries were compared to those without atherosclerosis. ANG II enhances mRNA synthesis and activity of MMP-2 in a p47phox-dependent manner. Immunohistochemical analyses revealed a co-localization of MMP-2 with p47phox, ANG II, AT1-receptor, and alpha-SMC actin. MMP-2 protein expression and gelatinolytic activity are increased in atherosclerotic arteries. Thus, activation of the renin-angiotensin system may contribute to plaque destabilization via ROS-dependent induction of MMP-2.
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PMID:Angiotensin II induces MMP-2 in a p47phox-dependent manner. 1567 Jul 68

Epigenetic control provides a mechanism for the reversible silencing of telomerase expression that occurs as a natural consequence of differentiation. Significant overlap between indirect telomerase regulation pathways and cell cycle checkpoint pathways exist, suggesting that these discrete genetic elements (namely, p21, p53, and hTERT) synergistically cooperate to inhibit tumorigenesis. Mutations in these pathways have been known to contribute to cancer formation. However, the incorporation of epigenetic regulatory mechanisms provides another line of defense against these negative occurrences. These proteins are also implicated in the process of senescence, caused in eukaryotic cell lines by telomere shortening. Although the debate continues, there is significant evidence to classify the process of cellular senescence as an in vitro model for human aging. In addition, the study of stem cells gives information about the down-regulation of hTERT in the aging process. Diseases such as Werner S syndrome, ATM (ataxia telangiectasia mutated kinase), DKC (dyskeratosis congenita), and atherosclerosis have been linked to aberrant telomerase expression and other aging-related tissue malfunctions could be related to the presence of senescent cells changing the cellular microenvironment. Therefore, restoring telomerase activity as a putative therapeutic strategy necessitates further study to elucidate the intricacies linking genetic and epigenetic modulations of hTERT.
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PMID:Epigenetic control of telomerase and modes of telomere maintenance in aging and abnormal systems. 1576 67

Inflammation is a key event in the development of atherosclerosis. Nuclear factor-kappaB (NF-kappaB) is important in the inflammatory response regulation. The effector peptide of the renin angiotensin system Angiotensin II (Ang II) activates NF-kappaB and upregulates some related proinflammatory genes. Our aim was to investigate whether other angiotensin-related peptides, as the N-terminal degradation peptide Ang IV, could regulate proinflammatory factors (activation of NF-kappaB and related genes) in cultured vascular smooth muscle cells (VSMCs). In these cells, Ang IV increased NF-kappaB DNA binding activity, caused nuclear translocation of p50/p65 subunits, cytosolic IkappaB degradation and induced NF-kappaB-dependent gene transcription. Ang II activates NF-kappaB via AT1 and AT2 receptors, but AT1 or AT2 antagonists did not inhibit NF-kappaB activation caused by Ang IV. In VSMC from AT1a receptor knockout mice, Ang IV also activated NF-kappaB pathway. In those cells, the AT4 antagonist divalinal diminished dose-dependently Ang IV-induced NF-kappaB activation and prevented IkappaB degradation, but had no effect on the Ang II response, indicating that Ang IV activates the NF-kappaB pathway via AT4 receptors. Ang IV also increased the expression of proinflammatory factors under NF-kappaB control, such as MCP-1, IL-6, TNF-alpha, ICAM-1, and PAI-1, which were blocked by the AT4 antagonist. Our results reveal that Ang IV, via AT4 receptors, activates NF-kappaB pathway and increases proinflammatory genes. These data indicate that Ang IV possesses proinflammatory properties, suggesting that this Ang degradation peptide could participate in the pathogenesis of cardiovascular diseases.
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PMID:Angiotensin IV activates the nuclear transcription factor-kappaB and related proinflammatory genes in vascular smooth muscle cells. 1583 14

Current understanding of the genesis of diabetic vascular disease suggests that vascular complications, such as atherosclerosis and hypertension, are associated with changes in structural and functional parameters. Experimental and epidemiological data suggest that activation of the renin-angiotensin-aldosterone system plays an important role in the development of micro- and macro-vascular complications. Most of the negative cardiovascular actions of angiotensin II are mediated through AT1 receptors, whereas the AT2 receptors mediate largely beneficial effects. Hence, compared to angiotensin converting enzyme inhibitors (ACEIs), selective AT1 receptor blockers (ARBs) should provide additional end organ protection via AT2 receptors activation. Although ACEIs are useful therapeutically, they are being currently displaced by ARBs. Enhanced calcium ion channel activity is reported in vascular smooth muscles from diabetic animal models. Clinical benefits of calcium channel blockers (CCBs) in diabetic hypertensive patients are controversial, but there is increasing experimental evidence for the beneficial effects of dihydropyridine-type CCBs. Although the treatment of hypertension in diabetics reduces cardiovascular and microvascular complications, the ideal strategy for treating hypertension in diabetics has not been well defined and warrants a combination approach. Only limited clinical data regarding the use of ARBs in combination with CCBs in diabetics are available. The experimental data suggest that combination of a CCB and an AT1 receptor blocker, or a hypothetical dual blocker of AT1 receptors as well as of calcium channels would be an ideal regimen. There is, however, no conclusive clinical evidence to support the combined use of these drugs. This review highlights the available experimental data that support the therapeutic benefits of this combination.
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PMID:Saga of renin-angiotensin system and calcium channels in hypertensive diabetics: does it have a therapeutic edge? 1600 28

Type 2 diabetes is a cardiovascular disease equivalent that is associated with accelerated atherosclerosis and significant mortality. However, the metabolic syndrome and prediabetes are associated with increased cardiovascular mortality, indicating that atherogenic vascular changes begin prior to the onset of overt diabetes. At the core of diabetes and the metabolic syndrome is insulin resistance (IR), which sets the stage for dyslipidemia, hypertension, and inflammation. Endothelial dysfunction is the first stage of the atherosclerosis process and results from exposure to cardiovascular risk factors, such as IR and diabetes. IR and atherosclerosis follow parallel paths as they progress in severity. Thiazolidinediones, angiotensin-converting enzyme inhibitors, angiotensin receptor-AT1 blockers, and statins are widely used in the treatment of diabetes. Emerging evidence indicates that these pharmacologic agents have added mechanisms of action, especially on the endothelium and in the prevention of diabetes.
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PMID:Insulin resistance and the endothelium. 1603 73

The endothelium is a favourite early target of cardiovascular risk factors and cardiovascular diseases like hypertension. This key role of the endothelium results from its capacity to respond to numerous autocrine and paracrine stimuli and to mechanical factors like shear stress but also from the pathophysiological consequences of endothelial dysfunction on vasomotor tone, arterial stiffness, arterial remodelling, and inflammation, all of which are factors that play a critical role in atherosclerosis and target-organ damage. In hypertension, endothelial dysfunction has been shown at the level of both resistance and conduit arteries and mainly results from an increase in nitric oxide (NO) degradation by interaction between NO and superoxide anions, while in experimental models of hypertension a decrease in NO production can also be observed. The fact that forearm endothelial dysfunction is a marker of future cardiovascular events in patients with hypertension stresses the importance of the clinical evaluation of endothelial function and of the evaluation of the effects of the different antihypertensive drug classes on this parameter. In this context, many studies have demonstrated that angiotensin-converting enzyme inhibitors, the perindopril-indapamide combination, and angiotensin II type I receptor (AT1) blockers improve endothelium-dependent vasodilatation partly independently of arterial pressure. Both their antioxidant effects and the stimulation of the release of NO are involved in their beneficial effects. For calcium antagonists, only the recent drugs have been shown to improve endothelial function with a simultaneous improvement in several markers of oxidative stress. Finally, beta-blockers classically do not affect endothelial function. Only nebivolol, a beta-blocker with NO donor properties, has been shown to improve endothelial function, but this effect results from the increase in NO and not from the beta-blocking properties of the drug.
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PMID:Targeting endothelial dysfunction in hypertensive subjects. 1607 29

Atherosclerotic plaque rupture is promoted by metalloproteinase (MMP)-2 and MMP-9, enzymes that degrade the fibrous cap leading to plaque erosion. MMP biosynthesis is mediated by prostaglandin (PG)E2, the product of cyclooxygenase (COX)-2/inducible PGE synthase (mPGES) activity. We have recently reported the overexpression of COX-2/mPGES-1 in vulnerable plaques as a basis of MMP-mediated plaque instability. Hypercholesterolemia and hypertension are two important risk factors for atherosclerosis. Recent trial showed that statins and AT1 receptor blockers significantly reduce the incidence of cardiovascular events in humans. Since anti-inflammatory effects have been reported in association to therapy with statins or AT1 receptor blockers, in two different studies we hypothesized that these drugs can stabilize atherosclerotic plaques through modulation of COX-2/mPGES-1-dependent MMP biosynthesis. Our data demonstrated the stabilizing effect of atherosclerotic plaques by simvastatin or irbesartan, that is due, at least in part, to the reduction of inflammatory burden and suppression of PGE2-dependent metalloproteinases release.
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PMID:Pharmacological modulation of plaque instability. 1621 85

The biological actions of angiotensin II (ANG), the most prominent hormone of the renin-angiotensin-aldosterone system (RAAS), may promote the development of atherosclerosis in many ways. ANG aggravates hypertension, metabolic syndrome, and endothelial dysfunction, and thereby constitutes a major risk factor for cardiovascular disease. The formation of atherosclerotic lesions involves local uptake, synthesis and oxidation of lipids, inflammation, as well as cellular migration and proliferation--mechanisms that may all be enhanced by ANG via its AT1 receptor. ANG may also increase the risk of acute thrombosis by destabilizing atherosclerotic plaques and enhancing the activity of thrombocytes and coagulation. After myocardial infarction, ANG promotes myocardial remodeling and fibrosis, and its many pathological mechanisms deteriorate the prognosis of these high-risk patients in particular. Therapeutically, inhibitors of the angiotensin I-converting enzyme (ACEI) and AT1 receptor blockers (ARB) are available to suppress the generation and cellular signaling of ANG, respectively. Despite major differences in the efficacy of ANG suppression and the modulation of other hormones and receptors, both classes of drugs are generally effective in attenuating numerous pathomechanisms of ANG in vitro, and in diminishing the development of atherosclerotic lesions and restenosis after angioplasty in various animal models. In clinical therapy, ACEI and ACE are well-tolerated antihypertensive drugs that also improve the prognosis of heart failure patients. After myocardial infarction and in stable coronary heart disease, ACEI have been shown to reduce mortality in a manner independent of hemodynamic alterations. However, there is little evidence that inhibitors of the RAAS may be effective against arterial restenosis, and a possible benefit of these substances compared to other antihypertensive drugs in the primary prevention of coronary heart disease in hypertensive patients is still a matter of debate, possibly depending on the specific substance and condition being investigated. As such, the general clinical efficacy of ACEI and ARB may be due to a positive influence on hemodynamic load, vascular function, myocardial remodeling, and neuro-humoral regulation, rather than to a direct attenuation of the atherosclerotic process. Further therapeutic advances may be achieved by identifying optimum drugs, patient populations, and treatment protocols.
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PMID:ACE inhibitors and angiotensin II receptor antagonists. 1659 9

Asymmetric dimethylarginine (ADMA) is synthesized during the methylation of protein arginine residues by protein arginine methyltransferases (PRMT) and is released during proteolysis. ADMA is a competitive inhibitor of nitric oxide synthase and may decrease NO availability. ADMA is eliminated by renal excretion or is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) to citruline and dimethylamine. Two other endogenous methylarginines are also synthesized by PRMT: N-monomethyl-L-arginine (L-NMMA) and symmetric dimethylarginine (SDMA). L-NMMA inhibits NO synthase but its concentrations in circulation are much lower than ADMA whereas SDMA is inactive. Plasma concentration of ADMA is markedly increased in patients with chronic renal failure and moderately increased in patients with many other diseases including hyperlipidemia, diabetes mellitus, arterial hypertension, hyperhomocysteinemia and heart failure. The increased concentration of ADMA is positively correlated with markers of atherosclerosis, such as carotid artery intima-media thickness and has a predictive value for acute cardiovascular events in prospective studies. Angiotensin-converting enzyme inhibitors, angiotensin AT1 receptor antagonists, vitamin E and, according to some studies, estrogens used in hormonal replacement therapy reduce plasma ADMA concentration, which may contribute to their beneficial effect on NO synthesis and endothelial function. However, in some states associated with excess of NO, such as septic shock or excitotoxic neuronal injury ADMA may be protective by limiting toxic effect of high concentrations of NO. This article reviews the effect of pharmacotherapy on ADMA metabolism and its possible clinical implications.
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PMID:Asymmetric dimethylarginine (ADMA) as a target for pharmacotherapy. 1670 18

Ca2+ channels are involved in the regulation of vascular functions. Angiotensin II is implicated in the development of atherosclerosis and vascular remodeling. In this study, we demonstrated that angiotensin II preferentially increased the expression of alpha1G, a T-type Ca2+ channel subunit, via AT1 receptors in endothelial cells. Angiotensin II-induced expression of alpha1G was inhibited by pretreatment with atorvastatin and the MEK1/2 inhibitor, PD98059. The effect of atorvastatin was reversed by mevalonate and farnesyl pyrophosphate which implicates the activation of the small GTP-binding protein, Ras. Our data indicate that angiotensin II induces alpha1G expression in endothelial cells via AT1 receptors, Ras and MEK. Angiotensin II-induced migration of endothelial cells in a wound healing model was inhibited by incubation with mibefradil, a T-type Ca2+ channel blocker. Our data indicate that angiotensin II induces T-type Ca2+ channels in endothelial cells, which may play a role in the development of vascular disorders.
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PMID:Atorvastatin inhibits angiotensin II-induced T-type Ca2+ channel expression in endothelial cells. 1684 60


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