Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glyceryl trinitrate (GTN) is used in the treatment of angina pectoris and cardiac failure, but the rapid onset of GTN tolerance limits its clinical utility. Research suggests that a principal cause of tolerance is inhibition of an enzyme responsible for the production of physiologically active concentrations of NO from GTN. This enzyme has not conclusively been identified. However, the mitochondrial aldehyde dehydrogenase (ALDH2) is inhibited in GTN-tolerant tissues and produces NO2- from GTN, which is proposed to be converted to NO within mitochondria. To investigate the role of this enzyme in GTN tolerance, cumulative GTN concentration-response curves were obtained for both GTN-tolerant and -nontolerant rat aortic rings treated with the ALDH inhibitor cyanamide or the ALDH substrate propionaldehyde. Tolerance to GTN was induced using both in vivo and in vitro protocols. The in vivo protocol resulted in almost complete inhibition of ALDH2 activity and GTN biotransformation in hepatic mitochondria, indicating that long-term GTN exposure results in inactivation of the enzyme. Treatment with cyanamide or propionaldehyde caused a dose-dependent increase in the EC50 value for GTN-induced relaxation of similar magnitude in both tolerant and nontolerant aorta, suggesting that although cyanamide and propionaldehyde inhibit GTN-induced vasodilation, these inhibitors do not affect the enzyme or system involved in tolerance development to GTN. Treatment with cyanamide or propionaldehyde did not significantly inhibit 1,1-diethyl-2-hydroxy-2-nitrosohydrazine-mediated vasodilation in tolerant or nontolerant aorta, indicating that these ALDH inhibitors do not affect the downstream effectors of NO-induced vasodilation. Immunoblot analysis indicated that the majority of vascular ALDH2 is present in the cytoplasm, suggesting that mitochondrial biotransformation of GTN by ALDH2 plays a minor role in the overall vascular biotransformation of GTN by this enzyme.
Mol Pharmacol 2003 Nov
PMID:Role of mitochondrial aldehyde dehydrogenase in nitrate tolerance. 1457 60

Attenuation correction may improve the diagnostic accuracy of myocardial perfusion imaging (MPI). However, few studies have dealt with the clinical consequences for reporting. We compared routine reports based on scatter-corrected MPI (MPI-routine) with consensus readings of scatter-corrected (MPI-scatter) and scatter plus attenuation-corrected studies (MPI-attenuation) to investigate the impact of attenuation correction on reporting. One hundred consecutive stable angina patients (including 55 men) were investigated in a 99mTc-sestamibi 2-day gated protocol with scatter and attenuation correction. With MPI-routine, 53 patients had normal perfusion and 47 abnormal perfusion, compared to 62 and 38 with MPI-attenuation, and 54 and 46, respectively, with MPI-scatter. Agreement between MPI-routine and MPI-attenuation with respect to overall diagnosis (normal/abnormal perfusion) was 89% (kappa=0.78) compared to 95% (kappa=0.90) between MPI-routine and MPI-scatter. With MPI-attenuation, the overall routine diagnosis changed in 11 patients, of which ten cases were judged normal after scatter plus attenuation correction. The majority of the "normalised" studies were among patients with apparently single-vessel RCA disease as judged from MPI. Agreement rates with regard to normal, reversible or irreversible defects between MPI-attenuation and MPI-routine for the LAD, LCX and RCA territories were 88%, 97% and 85%, respectively, without significant sex differences. In conclusion, attenuation correction caused a change in diagnosis in approximately 10% of the patients, corresponding to one-fifth of the abnormal studies. In all but one case, the shift was from abnormal to normal, mostly because of a different interpretation in the RCA territory.
Eur J Nucl Med Mol Imaging 2004 Aug
PMID:Scatter and attenuation correction changes interpretation of gated myocardial perfusion imaging. 1511 45

This review summarises the evidence for the role of myocardial perfusion scintigraphy (MPS) in patients with known or suspected coronary artery disease. It is the product of a consensus conference organised by the British Cardiac Society, the British Nuclear Cardiology Society and the British Nuclear Medicine Society and is endorsed by the Royal College of Physicians of London and the Royal College of Radiologists. It was used to inform the UK National Institute of Clinical Excellence in their appraisal of MPS in patients with chest pain and myocardial infarction. MPS is a well-established, non-invasive imaging technique with a large body of evidence to support its effectiveness in the diagnosis and management of angina and myocardial infarction. It is more accurate than the exercise ECG in detecting myocardial ischaemia and it is the single most powerful technique for predicting future coronary events. The high diagnostic accuracy of MPS allows reliable risk stratification and guides the selection of patients for further interventions, such as revascularisation. This in turn allows more appropriate utilisation of resources, with the potential for both improved clinical outcomes and greater cost-effectiveness. Evidence from modelling and observational studies supports the enhanced cost-effectiveness associated with MPS use. In patients presenting with stable or acute chest pain, strategies of investigation involving MPS are more cost-effective than those not using the technique. MPS also has particular advantages over alternative techniques in the management of a number of patient subgroups, including women, the elderly and those with diabetes, and its use will have a favourable impact on cost-effectiveness in these groups. MPS is already an integral part of many clinical guidelines for the investigation and management of angina and myocardial infarction. However, the technique is underutilised in the UK, as judged by the inappropriately long waiting times and by comparison with the numbers of revascularisations and coronary angiograms performed. Furthermore, MPS activity levels in this country fall far short of those in comparable European countries, with about half as many scans being undertaken per year. Currently, the number of MPS studies performed annually in the UK is 1,200/million population/year. We estimate the real need to be 4,000/million/year. The current average waiting time is 20 weeks and we recommend that clinically appropriate upper limits of waiting time are 6 weeks for routine studies and 1 week for urgent studies.
Eur J Nucl Med Mol Imaging 2004 Feb
PMID:Myocardial perfusion scintigraphy: the evidence. 1512 10

The aim of this study was to assess the plasma levels of VEGF and interleukin-10 in patients with acute myocardial infarction (AMI) and stable chronic angina (SA) and correlate the values with traditional CHD risk factors, left ventricular ejection fraction (LVEF) and established inflammatory marker hsCRP. Fifty patients with AMI and 30 with SA were enrolled. IL-10 levels in AMI patients were lower than in SA patients (9.81 +/- 5.0 versus 22.63 +/- 8.38 pg/ml, p < 0.00001). IL-10 levels were lower in AMI and SA patients with multiple CHD risk factors than in patients < or = 2 risk factors (SA: 19.48 +/- 2.94 versus 23.77 +/- 2.94 pg/ml; p < 0.005; AMI: 8.64 +/- 4.43 versus 11.85 +/- 4.09 pg/ml; p < 0.05) and patients with AMI and single-vessel than with multi-vessel disease (8.45 +/- 3.86 versus 10.72 +/- 3.95 pg/ml; p < 0.05). VEGF levels in AMI patients were higher than in SA patients (312.0 +/- 67.0 versus 221.0 + /- 50 pg/ml; p < 0.005). VEGF levels were higher in AMI patients with multi-vessel disease than in patients with single-vessel disease (348.74 +/- 45.23 versus 252.05 +/- 21.12 pg/ml; p < 0.005), with LVEF <40% and Killip class III-IV than in patients with LVEF >40% and Killip class I-II (338.8 +/- 51.59 versus 271.8 +/- 50.51 pg/ml; p < 0.005 and 340.71 +/- 52.94 versus 275.45 +/- 49.48 pg/ml; p < 0.05, respectively) and with chest pain > 6 h versus < 6 h (330.03 +/- 58.58 versus 292 +/- 57.53 pg/ml; p < 0.05). HsCRP concentrations in AMI patients were higher than in SA (1.24 +/- 0.47 versus 0.42 +/- 0.14; p < 0.0001). HsCRP was correlated with IL-10 (r = -0.413; p < 0.05) and VEGF (r = 0.319; p < 0.05). Acute myocardial infarction is associated with elevated VEGF levels and decreased concentration of IL-10. There is a significant correlation between levels of inflamatory markers and CHD risk factors and the function of the left ventricle on admission.
Int J Mol Med 2004 Aug
PMID:The pro- and anti-inflammatory markers in patients with acute myocardial infarction and chronic stable angina. 1525 85

Bioengineering the regenerative heart may provide a novel treatment for heart failure. On May 14, 2002, a 55-year-old man suffering from ischemic myocardial infarction received 25 injections carrying 465 million cGMP-produced pure myoblasts into his myocardium after coronary artery bypass grafting. As on August 28, 2002, his EKG was normal and showed no arrhythmia. His ejection fraction increased by 13%. He no longer experienced shortness of breath and angina as he did before the treatment. Three myogenesis mechanisms were elucidated with 17 human/porcine xenografts using cyclosporine as immunosuppressant. Some myoblasts developed to become cardiomyocytes. Others transferred their nuclei into host cardiomyocytes through natural cell fusion. As yet others formed skeletal myofibers with satellite cells. De novo production of contractile filaments augmented the heart contractility. Human myoblasts transduced with VEGF165 gene produced six times more capillaries in porcine myocardium than in placebo. Xenograft rejection was not observed for up to 20 weeks despite cyclosporine discontinuation at 6 weeks. Pros and cons of autografts vs. allografts are compared to guide future development of heart cell therapy.
Mol Cell Biochem 2004 Aug
PMID:Human VEGF165-myoblasts produce concomitant angiogenesis/myogenesis in the regenerative heart. 1552 78

Emerging evidence has shown that administration of angiogenic growth factors, either as recombinant protein or by gene transfer, can augment tissue perfusion through neovascularization in animal models of myocardial and hindlimb ischemia. Many cytokines have angiogenic activity; one of those that have been best studied in animal models and clinical trials is vascular endothelial growth factor (VEGF). VEGF has been known to be a key regulator of physiologic and pathologic angiogenesis associated with tumor. Recently the effect of VEGF is not restricted to the direct angiogenic effect in vivo but includes mobilization of bone-marrow-derived endothelial progenitor cells and augmentation of postnatal vasculogenesis in situ. Clinical trials of therapeutic angiogenesis with VEGF in patients with end-stage coronary artery disease have shown increases in exercise time and reductions in anginal symptoms and have provided objective evidence of improved perfusion and left ventricular function. Larger scale placebo-controlled trials with recombinant protein (rhVEGF165) have been limited to intracoronary and intravenous administration and have shown favorable trends in exercise time and angina frequency. Small-scale, placebo-controlled, randomized clinical trials of gene transfer (phVEGF-2) via thoracotomy or percutaneous intramyocardial delivery demonstrated significant improvement of both subjective symptoms and objective measures of myocardial ischemia. Both therapeutic modalities appear to be safe and well tolerated. Further studies are required to determine the optimal dose, formulation, route of administration, and combinations of growth factors and the utility of adjunctive endothelial progenitor cell or other stem cell supplementation, to provide safe and effective therapeutic myocardial neovascularization.
Mol Cell Biochem 2004 Sep
PMID:Therapeutic myocardial angiogenesis with vascular endothelial growth factors. 1554 36

Unstable coronary syndromes, initiated by rupture of an atherosclerotic plaque, may involve the activation of matrix metalloproteinases (MMPs). The regulation of MMP activity is complex and involves three steps. First, an inactive pro-MMP is transcriptionally regulated, a process that is likely to involve the transcription factor activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappaB). Secondly, the pro-MMP is proteolytically cleaved into an active MMP. Plasmin has been suggested to be the major activator of MMPs in vivo. Thirdly, the activated MMP can be inhibited by tissue inhibitors of metalloproteinase (TIMPs). We investigated if expression of MMP9 and its potential regulators are induced in unstable coronary plaques. Atherosclerotic plaques from patients with stable (n=22) and unstable (n=39) angina were obtained by directional coronary atherectomy and analysed by semiquantitative RT-PCR and immunohisto-chemistry. Plasma was collected for ELISA analysis. mRNA for MMP9 as well as plasminogen activator inhibitor-1 (PAI-1) was increased in unstable plaques, while tissue type plasminogen activator (tPA) expression was similar in stable and unstable plaques. Plaques from unstable patients had an increased infiltration of macrophages and T-lymphocytes, nuclear localisation of AP-1 and the NF-kappaB subunit p65, as well as increased positive immunostaining for MMP9 and tPA. Plasma MMP9 antigen was elevated in unstable patients. MMP9 is expressed in the unstable coronary atherosclerotic plaque, as are its transcriptional and posttranscriptional regulators.
Int J Mol Med 2005 Jan
PMID:Expression of matrix metalloproteinase 9 and its regulators in the unstable coronary atherosclerotic plaque. 1558 28

A fatty acid analogue, 123I-labelled beta-methyl iodophenyl pentadecanoic acid (BMIPP), has been used to identify ischaemic and metabolically impaired myocardium. However, the prognostic value of BMIPP imaging, particularly in relation to stress myocardial perfusion imaging, remains unclear. Data from 167 consecutive patients with angina pectoris but without prior myocardial infarction (MI) who had undergone both BMIPP and stress 201Tl (sTL) imaging were analysed. Tracer uptake was graded using a 13-segment, 4-point scoring model. Patients were followed up for 48 months with primary end points (cardiac death, non-fatal MI) as hard cardiac events and with secondary end points (late revascularisation, recurrent angina and heart failure) as soft events. For overall cardiac events (5 hard and 29 soft events), Kaplan-Meier analysis revealed significantly lower event rates in subgroups with normal BMIPP uptake, a summed difference score of sTL (SDS) of <3 or absence of diabetes mellitus when compared to each counterpart. Multivariate Cox's analysis revealed reduced BMIPP uptake, SDS > or =3, diabetes and reduced ejection fraction to be significant predictors. Negative predictive values of normal BMIPP and SDS <3 for all events were 91% and 84%, respectively. No hard event occurred in 66 patients with normal BMIPP uptake, whereas two patients with SDS <3 but impaired BMIPP uptake had hard events. In conclusion, normal BMIPP imaging is an excellent prognostic sign, independently of stress myocardial perfusion imaging, in patients with angina pectoris without prior MI.
Eur J Nucl Med Mol Imaging 2004 Dec
PMID:Prognostic value of fatty acid imaging in patients with angina pectoris without prior myocardial infarction: comparison with stress thallium imaging. 1558 13

Platelet aggregation at the site of plaque rupture or erosion is a dominant feature in the pathophysiology of plaque destabilization. To elucidate the role of glycoprotein (GP) IIb/IIIa in coronary plaque destabilization, we immunohistochemically studied the presence of GP IIb/IIIa in coronary atherectomy specimens obtained from patients with stable angina (SAP) and unstable angina pectoris (UAP). Moreover, we immunohistochemically investigated the presence of P-selectin, which is known to be a marker of platelet activation, in these specimens. All these patients underwent atherectomy at primary atherosclerotic lesions responsible for SAP (n=25) and UAP (n=23). Frozen samples were studied with antibodies against smooth muscle cells, macrophages, neutrophils, endothelial cells, GP IIb/IIIa and P-selectin. Immunoreactive positive areas for GP IIb/IIIa, P-selectin, and macrophages, respectively, were calculated using computer-aided planimetry, and numbers of neutrophils were also counted. In the culprit lesions of UAP patients, 17 of the 23 lesions (74%) contained GP IIb/IIIa positive platelet thrombi, and all these platelet thrombi were positive for P-selectin. In contrast, in the lesions of SAP patients, 3 of the 25 lesions (12%) showed staining positivity for GP IIb/IIIa and P-selectin. Quantitatively, the percentage of GP IIb/IIIa- and P-selectin-positive area was significantly higher (GP IIb/IIIa, P<0.0005; P-selectin, P<0.0001) in patients with UAP than in patients with SAP. The number of neutrophils was significantly higher (P<0.0005) in patients with UAP than in patients with SAP. Moreover, the percentage of GP IIb/IIIa-positive area showed a significant positive correlation with the number of neutrophils (r=0.66, p<0.0001). These findings strongly suggest that platelet activation and aggregation, leading to formation of platelet thrombi, and the interaction between activated platelets and neutrophils play a pivotal role in the pathogenesis of plaque destabilization in human coronary atherosclerotic lesions.
Int J Mol Med 2005 Apr
PMID:Immunolocalization of platelet glycoprotein IIb/IIIa and P-selectin, and neutrophil-platelet interaction in human coronary unstable plaques. 1575 16

Coronary vasospasm appears to play a significant role in the etiology of myocardial ischemia in patients with hypertrophic cardiomyopathy (HCM). Furthermore, the management of patients with coexistent HCM and coronary spastic angina (CSA) presents a therapeutic challenge. The purpose of this study was to examine the Glu298Asp variant of the endothelial nitric oxide synthase (eNOS) gene to determine whether this polymorphism was associated with susceptibility to CSA in patients with HCM. The eNOS gene polymorphism (Glu298Asp) was genotyped in 150 HCM patients by the TaqMan chemical method. Patients were classified into group A (n=12) if they had CSA provoked by intracoronary acetylcholine, and group B (n=138) if they did not. In group A, the frequency of Glu/Glu, Glu/Asp, and Asp/Asp genotypes was 5 (41.7%), 6 (50%), and 1 (8.3%), respectively. In group B, it was 119 (86.2%), 17 (12.3%), and 2 (1.5%), respectively. The frequency of the Asp298 variant was significantly higher in group A than in group B (P<0.001). Multivariate logistic regression analysis showed that the Asp298 variant was a significant risk factor for CSA (odds ratio 11.8; P<0.001) that was independent of age, gender, smoking status or body mass index. Significantly more drugs were used by the patients in group A than those in group B and the patients with the Asp298 variant were treated with significantly more drugs than those without it. In conclusion, the Asp298 variant of the eNOS gene may be associated with CSA in HCM patients. HCM patients with CSA or the Asp298 variant may need more drugs to relieve their symptoms.
J Mol Med (Berl) 2005 Aug
PMID:Endothelial nitric oxide synthase gene polymorphism (Glu298Asp) in patients with coexistent hypertrophic cardiomyopathy and coronary spastic angina. 1577 8


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