Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated levels of tumor necrosis factor-alpha (TNF), a proinflammatory cytokine, are associated with coronary artery disease. However, it is unclear whether vasodilator function of coronary resistance arterioles is susceptible to TNF. Herein, we examined whether TNF can affect endothelium-dependent nitric oxide (NO)-mediated dilation of coronary arterioles to adenosine and whether inflammatory signaling pathways such as mitogen-activated protein kinases, ceramide sphingolipids, and oxidative stress are involved in the TNF-mediated effect. To eliminate confounding influences associated with in vivo preparations, coronary arterioles from porcine heart were isolated and pressurized without flow for in vitro study. Intraluminal treatment with TNF (1 ng/ml, 90 min) significantly attenuated the NO release and vasodilation to adenosine. This inhibitory effect was not observed in denuded vessels or in the presence of NO synthase inhibitor l-NMMA. Histochemical data showed that superoxide production and JNK phosphorylation in arteriolar endothelial cells was enhanced by TNF. Administration of superoxide scavenger or inhibitors of ceramide-activated protein kinase (dimethylaminopurine), JNK (SP600125 and dicumarol), and xanthine oxidase (allopurinol) reduced superoxide production as well as restored NO release and vasodilation to adenosine. Conversely, the effects of TNF were insensitive to inhibitors of p38 (SB203580), ERK (PD98059), NAD(P)H oxidase (apocynin), or mitochondrial respiratory chain (rotenone). These data indicate that TNF inhibits endothelium-dependent NO-mediated dilation of coronary arterioles by ceramide-induced activation of JNK and subsequent production of superoxide via xanthine oxidase. Because myocardial ischemia augments adenosine production and elevates TNF level, inhibiting adenosine-stimulated endothelial release of NO by TNF could contribute to inadequate regulation of coronary blood flow during the development of ischemic heart disease.
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PMID:Activation of JNK and xanthine oxidase by TNF-alpha impairs nitric oxide-mediated dilation of coronary arterioles. 1641 74

While statin treatment may transiently mobilize endothelial progenitor cells (EPCs), the dose-dependent effects of a continuous statin therapy on EPCs in patients with chronic coronary artery disease (CAD) have not been analyzed. In 209 patients with angiographically documented CAD, 144 of which received 10-40 mg/day of statins for >8 weeks, the EPC number was determined by flow cytometry directly (CD34(+)/KDR(+), n=58) and after in vitro-culture (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-labeled Ac-LDL (DiI-Ac-LDL(+))/lectin(+), n=209). EPC function was assessed by the formation of colony forming units (CFUs). Univariate analysis revealed that the dose of continuous statin therapy inversely correlated with the EPC number. Treatment with 40 mg/day significantly reduced EPC counts. Multivariate analysis unveiled the statin dose and extent of CAD as independent predictors of reduced EPC numbers. Conversely, obesity predicted increased counts, while CFU development was not detectable in all patients and augmented in females and smokers but not in statin-treated patients. Compared with matched controls, statin-treated patients showed significantly reduced absolute and relative EPC counts. In a prospective analysis, initiation of statin therapy significantly diminished the number of circulating and isolated EPCs after 3 but not after 1 month(s). Thus, the statin dose during chronic and continuous treatment independently predicts reduced numbers of circulating as well as isolated EPCs in patients with CAD.
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PMID:Reduced numbers of circulating endothelial progenitor cells in patients with coronary artery disease associated with long-term statin treatment. 1683

Bmx/Etk non-receptor tyrosine protein kinase has been implicated in endothelial cell migration and tube formation in vitro. However, the role of Bmx in vivo is not known. Bmx is highly induced in the vasculature of ischemic hind limbs. We used both mice with a genetic deletion of Bmx (Bmx-KO mice) and transgenic mice expressing a constitutively active form of Bmx under the endothelial Tie-2 enhancer/promoter (Bmx-SK-Tg mice) to study the role of Bmx in ischemia-mediated arteriogenesis/angiogenesis. In response to ischemia, Bmx-KO mice had markedly reduced, whereas Bmx-SK-Tg mice had enhanced, clinical recovery, limb perfusion, and ischemic reserve capacity when compared with nontransgenic control mice. The functional outcomes in these mice were correlated with ischemia-initiated arteriogenesis, capillary formation, and vessel maturation as well as Bmx-dependent expression/activation of TNF receptor 2- and VEGFR2-mediated (TNFR2/VEGFR2-mediated) angiogenic signaling in both hind limb and bone marrow. More importantly, results of bone marrow transplantation studies showed that Bmx in bone marrow-derived cells plays a critical role in the early phase of ischemic tissue remodeling. Our study provides the first demonstration to our knowledge that Bmx in endothelium and bone marrow plays a critical role in arteriogenesis/angiogenesis in vivo and suggests that Bmx may be a novel target for the treatment of vascular diseases such as coronary artery disease and peripheral arterial disease.
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PMID:Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis. 1693 10

Norepinephrine (NE) transporters (NETs) are high-affinity transport proteins that mediate the synaptic clearance of NE after vesicular release. NETs represent a major therapeutic target for antidepressants and are targets of multiple psychostimulants including amphetamine (AMPH) and cocaine. Recently, we demonstrated that syntaxin 1A (SYN1A) regulates NET surface expression and, through binding to the transporter's NH(2) terminus, regulates transporter catalytic function. AMPH induces NE efflux and may also regulate transporter trafficking. We monitored NET distribution and function in catecholaminergic cell lines (CAD) stably transfected with either full-length human NET (CAD-hNET) or with an hNET N-terminal deletion (CAD-hNETDelta(28-47) cells). In hNET-CAD cells, AMPH causes a slow and small reduction of surface hNET with a modest increase in hNET/SYN1A associations at the plasma membrane. In contrast, in CAD-hNETDelta(28-47) cells, AMPH induces a rapid and substantial reduction in surface hNETDelta(28-47) accompanied by a large increase in plasma membrane hNETDelta(28-47)/SYN1A complexes. We also found that AMPH in CAD-hNETDelta(28-47) cells induces a robust increase in cytosolic Ca2+ and concomitant activation of calcium/calmodulin-dependent protein kinase II (CaMKII). Inhibition of either the increase in intracellular Ca2+ or CaMKII activity blocks AMPH-stimulated hNETDelta(28-47) trafficking and the formation of hNETDelta(28-47)/SYN1A complexes. Here, we demonstrate that AMPH stimulation of CAMKII stabilizes an hNET/SYN1A complex. This hNET/SYN1A complex rapidly redistributes, upon AMPH treatment, when mechanisms supported by the transporter's NH2 terminus are eliminated.
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PMID:Amphetamine induces a calcium/calmodulin-dependent protein kinase II-dependent reduction in norepinephrine transporter surface expression linked to changes in syntaxin 1A/transporter complexes. 1703 5

The purposes of this investigation were to identify a zone of normality for ratings of perceived exertion (RPE) and to compare the RPE responses in patients with coronary artery disease to this zone. The zone was generated from RPE estimated during the last minute of each stage of a Bruce treadmill test in 44 normal adult men. RPE were regressed against the corresponding MET level for each exercise stage. The zone was established as the 95% confidence interval (CI) spanning the average RPE vs MET regression line. RPE estimated during the last 1.0 min. of a Bruce or Modified Balke treadmill test administered to adult men (n=37) with coronary artery disease were compared to the 95% CI zone. A total of 19 (51%) of the coronary artery disease patients estimated RPE during a progressively incremented treadmill test that were above the zone, indicating a comparatively greater than normal perception of strain for a given metabolic stress. The presently generated zone provides a practical use of RPE in the interpretation of clinical exercise tests.
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PMID:A normative zone of RPE ratings for use during graded exercise testing. 1756 21

The formation of micronuclei (MN) is extensively used in molecular epidemiology as a biomarker of chromosomal damage, genome instability, and eventually of cancer risk. The occurrence of MN represents an integrated response to chromosome-instability phenotypes and altered cellular viabilities caused by genetic defects and/or exogenous exposures to genotoxic agents. The present article reviews human population studies addressing the relationship between genetic polymorphisms and MN formation, and provides insight into how genetic variants could modulate the effect of environmental exposures to genotoxic agents, host factors (gender, age), lifestyle characteristics (smoking, alcohol, folate), and diseases (coronary artery disease, cancer). Seventy-two studies measuring MN frequency either in peripheral blood lymphocytes or exfoliated cells were retrieved after an extensive search of the MedLine/PubMed database. The effect of genetic polymorphisms on MN formation is complex, influenced to a different extent by several polymorphisms of proteins or enzymes involved in xenobiotic metabolism, DNA repair proteins, and folate-metabolism enzymes. This heterogeneity reflects the presence of multiple external and internal exposures, and the large number of chromosomal alterations eventually resulting in MN formation. Polymorphisms of EPHX, GSTT1, and GSTM1 are of special importance in modulating the frequency of chromosomal damage in individuals exposed to genotoxic agents and in unexposed populations. Variants of ALDH2 genes are consistently associated with MN formation induced by alcohol drinking. Carriers of BRCA1 and BRCA2 mutations (with or without breast cancer) show enhanced sensitivity to clastogens. Some evidence further suggests that DNA repair (XRCC1 and XRCC3) and folate-metabolism genes (MTHFR) also influence MN formation. As some of the findings are based on relatively small numbers of subjects, larger scale studies are required that include scoring of additional endpoints (e.g., MN in combination with fluorescent in situ hybridization, analysis of nucleoplasmic bridges and nuclear buds), and address gene-gene interactions.
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PMID:Genetic polymorphisms and micronucleus formation: a review of the literature. 1803 39

Genome-wide gene expression analysis using DNA microarray has a great advantage to identify the genes or specific molecular cascades involved in mental diseases, including major depression and suicide. In the present study, we conducted DNA microarray analysis of major depression using postmortem prefrontal cortices. The gene expression patterns were compared between the controls and subjects with major depression. As a result, 99 genes were listed as the differentially expressed genes in major depression, of which several genes such as FGFR1, NCAM1, and CAMK2A were of interest. Gene ontology analysis suggested an overrepresentation of genes implicated in the downregulation or inhibition of cell proliferation. The present results may support the hypothesis that major depression is associated with impaired cellular proliferation and plasticity. Comparison between the controls and suicide victims with major depression, bipolar disorder, or schizophrenia was also conducted in the present study. Two genes, CAD and ATP1A3, were differentially expressed in the three comparisons in the same direction. Interestingly, these two genes were also included in the differentially expressed 99 genes in major depression. It may be worth investigating the genes in relation to suicide or major depression.
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PMID:Gene expression profiling of major depression and suicide in the prefrontal cortex of postmortem brains. 1806 48

The purposes of this study were to identify a zone of normality based upon ratings of perceived exertion (RPE) and compare the RPE of women with coronary artery disease to this zone. 45 healthy women (34.8 +/- 9.1 yr.) completed a Bruce treadmill test. RPE were estimated during the last minute of each workload. The zone of normality was established as the 95% confidence interval spanning the average line when RPE was regressed against MET. 51 women (66.6 +/- 9.3 yr.) with coronary artery disease completed a symptom-limited treadmill test. 31 of the women with coronary artery disease were taking beta blockers. RPE were compared to the RPE/MET relation of the zone. 57% of the women with coronary artery disease estimated RPE above the zone during the treadmill test. RPE responses above the zone of normality indicate an elevated perceptual strain for a given energy expenditure (i.e., MET). The zone of normality might be used as an aid in discriminating between normal and abnormal RPE responses during graded treadmill tests by women with coronary artery disease.
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PMID:RPE-based zone of normality for use in evaluating graded exercise test responses in women. 1845 74

Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits. Therefore, identifying the molecular phenotypes that vary in response to changes in DNA and that also associate with changes in disease traits has the potential to provide the functional information required to not only identify and validate the susceptibility genes that are directly affected by changes in DNA, but also to understand the molecular networks in which such genes operate and how changes in these networks lead to changes in disease traits. Toward that end, we profiled more than 39,000 transcripts and we genotyped 782,476 unique single nucleotide polymorphisms (SNPs) in more than 400 human liver samples to characterize the genetic architecture of gene expression in the human liver, a metabolically active tissue that is important in a number of common human diseases, including obesity, diabetes, and atherosclerosis. This genome-wide association study of gene expression resulted in the detection of more than 6,000 associations between SNP genotypes and liver gene expression traits, where many of the corresponding genes identified have already been implicated in a number of human diseases. The utility of these data for elucidating the causes of common human diseases is demonstrated by integrating them with genotypic and expression data from other human and mouse populations. This provides much-needed functional support for the candidate susceptibility genes being identified at a growing number of genetic loci that have been identified as key drivers of disease from genome-wide association studies of disease. By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study. We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process.
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PMID:Mapping the genetic architecture of gene expression in human liver. 1846 17

Advanced glycation endproducts (AGEs) have been reported to play a role in neointimal formation and increase the rate of in-stent restenosis (ISR) in the diabetic coronary artery disease patients treated with stents, but the potential pathogenic mechanisms of AGEs in vascular smooth muscle cell proliferation remain unclear. We sought to determine the AGEs related pathobiological mechanism of diabetic vasculopathy. Rat aortic smooth muscle cell (RAoSMC) culture was done with different concentrations of AGEs and proliferation was assessed. Immunohistochemistry for receptor of AGEs (RAGE) was performed with human carotid atheroma. Western blotting was performed to assess the activation of MAP kinase system in the cultured RAoSMC. AGEs increased RAoSMC proliferation and were associated with increased phosphorylation of ERK and p38 kinase by time and dose dependent manner. The MAP kinase activity was decreased by RNA interference for RAGE. AGEs stimulation increased reactive oxygen species (ROS) generation in cultured RAoSMC. From this study it is concluded that AGEs played a key role in RAoSMC proliferation via MAP kinase dependent pathways. Activation of vascular smooth muscle cell (VSMC) proliferation by MAP kinase system and increased formation of ROS may be the possible mechanisms of AGEs induced diabetic vasculopathy.
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PMID:Pathobiological role of advanced glycation endproducts via mitogen-activated protein kinase dependent pathway in the diabetic vasculopathy. 1877 52


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