Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The emerging recognition that chronic obstructive pulmonary disease (COPD) is a complex disorder, characterized not only by local pulmonary inflammation, but also by systemic inflammation that might have an adverse impact on various extrapulmonary organs, such as the blood vessels and the heart, among others, emphasizes the need for new and more effective forms of therapy for this debilitating disorder. Fortunately, many of the 'standard' therapeutic options used to treat COPD have the potential to influence systemic inflammation. Moreover, several new therapeutic strategies aimed at controlling the underlying inflammatory processes of COPD more specifically are under development. Unfortunately, we still do not know whether treatment of lung inflammation decreases, for example, the risk of acute cardiac events, progression of atherosclerosis or thrombotic events. It is also unclear whether, alternatively, treatment of heart disease can affect the progression of lung disease. Nonetheless, initial data seem to indicate that drugs, such as statins, ACE inhibitors, AT1 receptor blockers and PPAR agonists, used to treat a co-morbid condition have the potential to benefit COPD patients.
 ...
PMID:Treating systemic effects of COPD. 1789 27

The AT1 receptor plays a pivotal role for the pathogenesis of hypertension and atherosclerosis. AT1 receptor expression is regulated posttranscriptionally via destabilization of the AT1 receptor mRNA by mRNA binding proteins. Recently, we identified calreticulin as a novel binding protein within the 3'untranslated region of the AT1 receptor mRNA. Calreticulin phosphorylation is essential for binding of the AT1 receptor mRNA. In crosslink experiments, we identified src kinase as the key enzyme for calreticulin phosphorylation. Overexpression of src sense DNA resulted in vascular smooth muscle cells (VSMC) in destabilization, overexpression of src antisense resulted in stabilisation of the AT1 receptor mRNA. Furthermore, phosphorylation/dephosphorylation sites of calreticulin and their impact on the AT1 receptor mRNA stability were investigated. VSMC were stimulated with AngII before tyrosine phosphorylation as well as serine phosphorylation of calreticulin were analysed via immunoprecipitation. Stimulation of VSMC with AngII resulted in enhanced tyrosine and reduced serine phosphorylation. Both effects are essential for AT1 mRNA stability as assessed by use of pharmacological inhibitors of serine dephosphorylation (cantharidin/ocadaic acid) or tyrosine phosphorylation (tyrphostin/orthovanadat). These findings imply an important role of serine dephosphorylation and tyrosine phosphorylation on calreticulin mediated AT1 receptor mRNA stability.
 ...
PMID:Differential phosphorylation of calreticulin affects AT1 receptor mRNA stability in VSMC. 1841 43

The renin-angiotensin system (RAS) modulates end-organ damages, resulting in cardiovascular and kidney diseases. Experiments both in vitro and in vivo demonstrate that the angiotensin II (Ang II) type 1 (AT1) receptor pathway also exerts pro-inflammatory and pro-atherogenic effects on bone marrow-derived cells (BMDCs). Here, we investigated how AT1 receptor expression by BMDCs contributes to atherosclerosis and kidney injury in vivo by transplanting BM into RAS-activated transgenic mice. There was no difference in the extent of kidney damage between mice receiving BM transplants from mutant mice lacking the angiotensin II type 1a receptor (AT1a) gene and mice receiving transplants from wild-type (WT) mice. However, mice receiving transplants from AT1a 'knockout' (KO) mice displayed accelerated lethality and atherosclerotic lesions. These results indicated that the effects of AT1a receptor on BMDCs are organ dependent. Microarray expression profiling of macrophages from AT1a-KO mice revealed significant changes in the mRNA levels for a number of genes implicated in atherosclerosis. In accordance with the in vivo atherosclerosis results, AT1a-KO macrophages exhibited greater uptake of modified lipoproteins relative to macrophages from WT mice. We propose that the expression of AT1a receptor by BMDCs limits atherosclerosis in vivo.
 ...
PMID:Deterioration of atherosclerosis in mice lacking angiotensin II type 1A receptor in bone marrow-derived cells. 1849 Aug 98

The defining characteristic of recessive disorders is the absence of disease in heterozygous carriers of the mutant alleles. However, it has been recognized that recessive carriers may differ from noncarriers in some phenotypes. Here, we studied ataxia telangiectasia (AT), a classical recessive disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. We compared the gene and microRNA expression phenotypes of noncarriers, AT carriers who have one copy of the ATM mutations, and AT patients with two copies of ATM mutations. We found that some phenotypes are more similar between noncarriers and AT carriers compared to AT patients, as expected for a recessive disorder. However, for some expression phenotypes, AT carriers are more similar to the patients than to the noncarriers. Analysis of one of these expression phenotypes, TNFSF4 level, allowed us to uncover a regulatory pathway where ATM regulates TNFSF4 expression through MIRN125B (also known as miR-125b or miR125b) [corrected] In AT carriers and AT patients, this pathway is disrupted. As a result, the level of MIRN125B is lower and the level of its target gene, TNFSF4, is higher than in noncarriers. A decreased level of MIRN125B is associated with breast cancer, and an elevated level of TNFSF4 is associated with atherosclerosis. Thus, our findings provide a mechanistic suggestion for the increased risk of breast cancer and heart disease in AT carriers. By integrating molecular and computational analyses of gene and microRNA expression, we show the complex consequences of a human gene mutation.
 ...
PMID:ATM gene mutations result in both recessive and dominant expression phenotypes of genes and microRNAs. 1867 48

Although the hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are widely used in atherosclerosis to reduce serum cholesterol, statins have multiple other effects, including direct effects on cells of the vessel wall. Recently, DNA damage, including telomere shortening, has been identified in vascular smooth muscle cells (VSMCs) in human atherosclerosis. Although statins reduce DNA damage in vitro, the mechanisms by which they might protect DNA integrity in VSMCs are unknown. We show that human atherosclerotic plaque VSMCs exhibit increased levels of double-stranded DNA breaks and basal activation of DNA repair pathways involving ataxia telangiectasia-mutated (ATM) and the histone H2AX in vivo and in vitro. Oxidant stress induced DNA damage and activated DNA repair pathways in VSMCs. Statin treatment did not reduce oxidant stress or DNA damage but markedly accelerated DNA repair. Accelerated DNA repair required both the Nijmegen breakage syndrome (NBS)-1 protein and the human double minute protein Hdm2, accompanied by phosphorylation of Hdm2, dissociation of NBS-1 and Hdm2, inhibition of NBS-1 degradation, and accelerated phosphorylation of ATM. Statin treatment reduced VSMC senescence and telomere attrition in culture, accelerated DNA repair and reduced apoptosis in vivo after irradiation, and reduced ATM/ATR (ATM and Rad3-related) activity in atherosclerosis. We conclude that statins activate a novel mechanism of accelerating DNA repair, dependent on NBS-1 stabilization and Hdm2. Statin treatment may delay cell senescence and promote DNA repair in atherosclerosis.
 ...
PMID:Statins use a novel Nijmegen breakage syndrome-1-dependent pathway to accelerate DNA repair in vascular smooth muscle cells. 1872 44

Angiotensin II (Ang II) not only mediates the effects of vasoconstriction and blood pressure regulation, but is also implicated in inflammation, endothelial dysfunction, atherosclerosis, hypertension and congestive heart failure. Ang 1I activates pathways of MAPK, NADPH and ROS, non-receptor tyrosine kinases and receptor tyrosine kinases via AT1 receptor to produce various effects involved in regulation of endothelial functions, endothelial dysfunction and vascular inflammation response.
 ...
PMID:[Progress in signal transduction pathways mediating effects of angiotensin II in endothelial cells]. 1881 91

The premature ageing ataxia telangiectasia (AT) and Werner syndromes (WS) are associated with accelerated cellular ageing. Young WS fibroblasts have an aged appearance and activated p38 MAP kinase, and treatment with the p38 inhibitor SB230580 extends their lifespan to within the normal range. SB203580 also extends the replicative lifespan of normal adult dermal fibroblasts, however, the effect is much reduced when compared to WS cells, suggesting that WS fibroblasts undergo a form of stress-induced premature senescence (SIPS). A small lifespan extension is seen in AT cells, which is not significant compared to normal fibroblasts, and the majority of young AT cells do not have an aged appearance and lack p38 activation, suggesting that the premature ageing does not result from SIPS. The lack of p38 activation is supported by the clinical manifestation, since AT is not associated with inflammatory disease, whereas WS individuals are predisposed to atherosclerosis, type II diabetes and osteoporosis, conditions known to be associated with p38 activation.
 ...
PMID:Assessing the role of stress signalling via p38 MAP kinase in the premature senescence of ataxia telangiectasia and Werner syndrome fibroblasts. 1883 Jun 81

Angiotensin (Ang)-converting enzyme (ACE) 2 cleaves Ang-II into the vasodilator peptide Ang-(1-7), thus acting as a pivotal element in balancing the local effects of these peptides. ACE2 has been identified in various tissues and is supposed to be a modulator of cardiovascular function. Decreases in ACE2 expression and activity have been reported in models of hypertension, heart failure, atherosclerosis, diabetic nephropathy and others. In addition, the expression level and/or activity are affected by other renin-angiotensin system components (e.g., ACE and AT1 receptors). Local inhibition or global deletion of brain ACE2 induces a reduction in baroreflex sensitivity. Moreover, ACE2-null mice have been shown to exhibit either blood pressure or cardiac dysfunction phenotypes. On the other hand, over-expression of ACE2 exerts protective effects in local tissues, including the brain. In this review, we will first summarize the major findings linking ACE2 to cardiovascular function in the periphery then focus on recent discoveries related to ACE2 in the CNS. Finally, we will unveil new tools designed to address the importance of central ACE2 in various diseases, and discuss the potential for this carboxypeptidase as a new target in the treatment of hypertension and other cardiovascular diseases.
 ...
PMID:Angiotensin-converting enzyme 2 in the brain: properties and future directions. 1901 90

Cellular senescence is a stress-response phenomenon in which cells lose the ability to proliferate; it is induced by telomere shortening, activation of oncogenes or tumor suppressor genes, or exposure to a sub-lethal dose of DNA damaging agents or oxidative stresses. cDNA microarray analysis reveals that the levels of interferons (IFNs) and IFN-inducible genes were altered during replicative senescence in human umbilical vascular endothelial cells (HUVECs). However, the role of IFNs in cellular senescence of HUVECs remains unidentified. This study demonstrated that prolonged treatment with IFN-gamma induced cellular senescence in HUVECs, as confirmed by G0/G1 cell cycle arrest, up-regulation of p53 and p21 protein levels, increased SA-beta-gal staining, and the accumulation of phospho-H(2)AX foci. IFN-gamma-induced cellular senescence was observed only in p16-knockdown cells or p16-null mouse embryonic fibroblasts (MEFs), but not in p53-knockdown cells or p53-null MEFs. IFN-gamma treatment increased ROS production, and an antioxidant, N-acetylcysteine, inhibited IFN-gamma-induced cellular senescence. Knockdown of ATM kinase or IFI16 rescued IFN-gamma-induced cellular senescence. Therefore, these results suggest that IFN-gamma might play an important role in cellular senescence through a p53-dependent DNA damage pathway and contribute to the pathogenesis of atherosclerosis via its pro-senescent activity.
 ...
PMID:Interferon-gamma induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells. 1907 Nov 56

While the renin-angiotensin system (RAS) is widely recognized to be involved in atherosclerosis, its potential role in the progression from atherosclerotic lesions to abdominal aortic aneurysm (AAA) is poorly understood. The present study aimed to investigate which components of the RAS may render the atherosclerotic aorta aneurysmatic. The expression of renin, prorenin/renin receptor, angiotensinogen, AT1- and AT2 receptors, cathepsin D, cathepsin G and chymase was examined by immunoblotting and immunohistochemistry in human atherosclerotic, aneurysmatic and healthy aortic tissues obtained from patients undergoing elective repair or at autopsy. AT1- and AT2 receptor mRNA expression was determined using quantitative real-time RT-PCR. All investigated local RAS components were up-regulated in atherosclerotic as compared to healthy tissues. AAA compared to atherosclerosis was characterized by a further increase in the expression of all RAS components except for the AT2 receptor. Cathepsin D was exclusively up-regulated in AAA. Most RAS components co-localized with infiltrating leukocytes or mast cells pointing to their contribution to inflammatory processes. Due to their proteolytic features, some RAS components (cathepsin D and cathepsin G and chymase) may contribute to AAA formation by accessory mechanisms. Taken together, our data suggest that in humans, RAS activation is not just a key-player in the pathogenesis of atherosclerosis, but that a further increasing activation may be involved in the transition from atherosclerosis to AAA.
Atherosclerosis 2009 Aug
PMID:Transition from atherosclerosis to aortic aneurysm in humans coincides with an increased expression of RAS components. 1919 79


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>