Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As a consequence of vessel wall injury, subendothelial matrix and collagen fibers are exposed to the flowing blood. Circulating platelets adhere to these structures and initiate arrest of blood flow. Subendothelial von Willebrand Factor (vWF) plays an important role in mediating platelet adhesion to the injured site, at least in the arterial circulation, characterized by sufficiently elevated shear forces to allow a critical conformation change in vWF, enabling an interaction between the vWF domain A1 and the vWF receptor on the platelet, the GPIb/IX complex. In vitro, in the absence of shear forces, non-physiological mediators are required to induce vWF binding to GPIb. Analysis of the mechanism according to which ristocetin induces vWF binding to GPIb revealed that 2 dimers of ristocetin simultaneously bind to vWF and GPIb, thus forming a quaternary complex in which repulsive negative charges are neutralized by the positively charged ristocetin. The interaction of vWF with its vascular receptor, i.e. collagen VI, which was isolated from human placenta and the extracellular matrix from lung fibroblasts, showed that vWF binds to collagen VI entirely via its A1 domain, i.e. via the domain that binds to GPIb. Also, vWF binding to intact extracellular matrices occurs to matrix associated collagen VI via the vWF A1 domain. By using a combination of 2 specific monoclonal anti-vWF antibodies, it was possible to induce conformational changes in WF that exposed the binding sequences in the A1 domain for GPIb. Thus, in the absence of shear forces, specific vWF binding to GPIb could be induced in the absence of any further mediators. This increased vWF binding to GPIb was sufficient to induce vWF dependent platelet aggregation, although as a consequence of Fc binding to the platelet Fc receptor, platelet activation also occurred via this pathway. Thus, general conformational changes in vWF suffice to expose the relevant amino acid sequences in the A1 domain that enable binding to GPIb. The collagen binding protein calin, isolated from the saliva of the medicinal leech, not only blocks platelet binding to collagen but also inhibited vWF binding. Thus this protein was able to inhibit both the vWF independent and vWF dependent platelet adhesion to various collagens, but much less the platelet binding to endothelial extracellular matrices, that contain matrix anchored vWF. In vivo anti-thrombotic studies in the hamster showed that the vWF antagonist aurin tricarboxylc acid was a more potent inhibitor of arterial thrombosis than of venous thrombosis, confirming the in vivo role of vWF during thrombus formation. Following vessel wall damage and thrombus formation, the neointima that formed in the hamster carotid artery developed more rapidly than in other models, and its formation partially responded to reported inhibitors of restenosis. The combination of cardiovascular drugs with complementary modes of action, such as G4120 (inhibitor of platelet GPIIb/IIIa and smooth muscle cell alpha(v) beta(3)) and quinapril (potent vascular ACE inhibitor) prevented neointima formation to about 70%, i.e. better than with any treatment separately.
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PMID:Platelet-vessel wall interactions in thrombosis and restenosis role of von Willebrand factor. 949 Sep 16

Do extremely old persons have a genetically favourable profile which has protected them from cardiovascular death? We have tried to answer this question by measuring DNA polymorphisms of selected cardiovascular risk indicators [factor VII, FVII (R/Q353, intron 7 (37bp)n, and -323ins10), beta fibrinogen (-455G/A), plasminogen activator inhibitor type 1, PAI-1 (-675(4G/5G)), tissue plasminogen activator, t-PA (intron 8 ins311), platelet receptor glycoprotein IIb/IIIa, GPIIb/IIIa (L/P33), prothrombin (20210G/A), methylene tetrahydrofolate reductase, MTHFR (A/V114), angiotensin converting enzyme, ACE (intron 16 ins287), and angiotensinogen (M/T235)]. Blood was collected from 187 unselected Danish centenarians, and 201 healthy Danish blood donors, aged 20-64 years (mean age 42 years). Genomic DNA was amplified using PCR and the genotype was determined by RFLP methods or allele-specific amplification followed by agarose gel electrophoresis. The frequencies of the high-risk alleles in centenarians were: for FVII R/Q353 0.91; for FVII intron 7 (37bp)n 0.67; for FVII-323 ins10 0.90; for fibrinogen 0.16; for PAI-1 0.52; for t-PA 0.59; for GPIIb/IIIa 0.16; for prothrombin 0.008; for MTHFR 0.33; for ACE 0.52; and for angiotensinogen 0.36. Comparable frequencies were observed in the blood donors. Subgroup analysis of men and women separately gave similar results. The genotype frequencies in the centenarians and the blood donors were similar for all polymorphisms, and this study suggests that common variations in genes associated with cardiovascular risk do not contribute significantly to longevity.
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PMID:Longevity is independent of common variations in genes associated with cardiovascular risk. 1049 71

Medical therapy of myocardial infarction has changed over the last 30 years. The "lag phenomenon", i.e. the time lapsing from the appraisal of a new, relevant scientific evidence and its practical adoption, has been variable, and different from one treatment to another. It has been very short for GP IIb/IIIa receptor inhibitors in candidates for urgent coronary angioplasty after myocardial infarction, short for ACE inhibitors, and it has been also short for the decrease in the prescription of calcium channel inhibitors after controversial scientific evidence. This time lapse has been long for beta-blockers, that only now are used quite extensively in Italy: from less than 10% of hospitalized patients during the early '80s, to over 60% nowadays. This evolution of medical therapy has been progressive and continuous, has not been divided into two eras, and thrombolysis seems to have little to do with it. The extensive introduction of thrombolysis has simply divided patients with acute myocardial infarction into two subgroups, very different for clinical characteristics: candidates for this therapy, and "others". Candidates for thrombolysis have a much better prognosis, but for a "paradox effect" they have been studied much more than the others. Now, the bulk of publications concerning patients undergoing thrombolysis carries the risk of spreading the concept that myocardial infarction has changed. We do not think that this corresponds to reality. Probably, the concepts that have guided medical therapy have been very similar and unchanged over the years, and both medical and surgical plus coronary angioplasty therapies are today much more appropriately used than yesterday.
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PMID:[From the great clinical studies to the management of the single patient. Medical therapy in the pre- and post-fibrinolytic era]. 1090 34

The general pharmacotherapeutic issues surrounding AMI are complex and expanding, especially with regard to treatment aimed at the [table: see text] culprit, coronary atherosclerotic thrombus. Basic, well-established therapy includes the routine administration of oxygen, nitroglycerin, aspirin, and at times morphine, with selected cases invoking caution with respect to these agents (e.g., nitroglycerin and the risk of hypotension in right ventricular infarction; contraindication to nitrolycerin in patients on sildenafil). Cardioprotective agents, especially beta-adrenergic antagonists, should be considered early in light of their demonstrated benefit; others, such as ACE inhibitors, need not be administered in the ED. Heparin, both UFH and the newer LMWHs, have well-established roles in acute coronary syndromes. The GP IIb/IIIa inhibitors are the most recent addition to the pharmacologic armamentarium; their role is evolving rapidly as research on this frontier continues. Table 2 reviews recommended dosing of selected agents in acute coronary syndromes.
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PMID:General pharmacologic treatment of acute myocardial infarction. 1137 87

To whatever extent the improvement in symptoms and survival rendered by treatment with ACE inhibitors is attributable to their effects on the circulation and the kidneys, this benefit can be rescinded by concomitant administration of aspirin. Although some useful prostaglandin-independent actions may persist, shutting down the entire prostaglandin system and trading off a substantial portion of the potential risk reduction with forfeit of salutary hemodynamic and renal effects is a high price to pay just to suppress production of TXA2. In patients requiring treatment for heart failure, if possible, aspirin should be avoided and the integrity of prostaglandin metabolism respected; the severer the heart failure the more compelling. There are other ways to inhibit platelet aggregation, some equally effective or even better than aspirin. Orally active platelet glycoprotein IIb/IIIa receptor antagonists, which may be more efficient than aspirin, have been developed and are now in clinical testing. Ticlopidine and clopidogrel, although more expensive than aspirin, are as easy to use and at least as effective as aspirin. Finally, because patients with severer heart failure are likely to be those with very low ejection fractions, these patients are good candidates for oral anticoagulation even though this treatment requires additional monitoring.
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PMID:Controversies in heart failure. Are beneficial effects of angiotensin-converting enzyme inhibitors attenuated by aspirin in patients with heart failure? 1171 80

Diabetes mellitus is a metabolic disease with explicit complications on coronary vascular system. The incidence of coronary disease is rising in type 1 as well as in type 2 diabetes mellitus, and it is caused by precipitating atherosclerosis. It is unquestionable that disorders of different metabolic pathways cause acute coronary syndrome, the same holding true for postinfarction complications. Strict blood glucose control (glucose value should be close to the physiologic values) is imperative not only in the prevention but also in the treatment of acute coronary syndrome and prevention of reinfarction. It is obvious that medicamentous and surgical treatment of coronary heart disease in diabetic patients can reduce morbidity and mortality. The treatment of acute coronary heart syndrome in diabetic patients is very similar to that in nondiabetic patients, however, it demands extra efforts to establish good metabolic control. Due to more than one narrowing of coronary arteries in diabetic patients, angioplasty is often less efficient and there is a need of specific evaluation by a cardio-cardio surgical team to choose the method of treatment: stent implantation or arterial bypass. The strategy of optimal revascularization for diabetic patients who have multivascular coronary heart disease is still controversial. Although data on early percutaneous or surgical revascularization show longterm benefit, the early studies were carried out before the extensive use of intracoronary stents and thrombocyte inhibitors GP IIb/IIa. A dilemma about this question showed up when excellent results of drug eluting intracoronary stents brought up credibility of compared studies. For best patient selection, it has been recommended that decision should be based more on coronary anatomy rather than the presence or absence of diabetes mellitus. Surgical revascularization (CAGB) should be considered in patients with diabetes mellitus who have stenosis of the left main coronary artery, significant diffuse stenosis involving each of epicardial vessels, and patients who have mild to significant left ventricular systolic dysfunction. Patients with a relatively focal nature of the disease and free from left main coronary artery or confluence of front left descendent artery could be considered for PCI (primary coronary intervention). When stents become widely available, patients would probably request PCI first instead of CABG. It is very important to remember that irrespective of PCI or CABG being preferred in diabetic patients, the role of drug therapy is enormous. Due to the diabetic patient susceptibility to fast progression of the disease and plaque rupture, drug therapy is indispensable in this population, e.g., aspirin, clopidogrel, 3-hydroxy-3-methylglytaryl-coenzyme A (HMGCoA) inhibitor reductase and ACE-inhibitor.
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PMID:[Acute coronary syndrome in diabetes]. 1520 3

We have investigated the frequencies of seven markers among 100 unrelated individuals with angiographically documented CAD (Coronary Artery Disease) and among 100 unrelated healthy blood donors in the central region of Corsica island (France). The seven polymorphisms analyzed were chosen from six candidate genes involved in (1) Renin-Angiotensin system: Angiotensin converting enzyme (ACE I/D), (2) Lipid metabolism: Cholesterol Ester Transfer Protein gene (CETP TAQ1B), (3) Platelet aggregation: alpha and beta subunits of the platelet GpIIb/GpIIIa integrin complex (GpIIb HPA3 and GpIIIa Pl(A1/A2)), (4) Coagulation fibrinolysis: Plasminogen Activator Tissue (PLAT TPA25 I/D) and Methylenetetrahydrofolate Reductase (MTHFR C677T and A1298C). The samples were genotyped using the polymerase chain reaction followed by restriction enzyme analysis for the RFLPs. No significant difference in allele frequencies between patient and control groups was observed. The occurrence of the MTHFR T677T genotype and of the T677T/A1298A compound genotype is higher in cases (20%) than in the controls (4%). Odds ratio seems to indicate that individuals with the MTHFR T677T genotype and the T677T/A1298A compound genotype had a 6-fold increased risk for developing CAD (ORs = 6; 95% CIs = 1.96-18.28) suggesting a possible association of MTHFR C677T with the risk of CAD in Corsican population.
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PMID:Prevalence of genetic risk factors for coronary artery disease in Corsica island (France). 1624 96

This paper provides a comprehensive up-to-date review of the medical and invasive management of patients with non- ST-segment elevation acute coronary syndromes (NSTE-ACS). The authors have summarized findings from key clinical trials published recent years that contribute to clinicians' understanding of how best to optimize therapy. The goals for the management of NSTE-ACS are rapid and accurate risk stratification, appropriate and institution-specific triage to interventional versus medical strategies and optimal pharmacologic therapy--all of which provide for a smooth and seamless transition of care between the emergency department and the cardiology service. High-risk features or absolute treatment trigger criteria that support more aggressive medical therapy (i.e., addition of small-molecule GP IIb/IIIa inhibitor to a core regimen of aspirin, enoxaparin, and in most cases, clopidogrel) and/or that would direct clinicians toward percutaneous, mechanical/interventional strategies as the preferred modality include, but are not limited to, the presence of one or more of the following: (1) elevated cardiac markers (troponin and/or CK-MB); (2) elevated levels of inflammatory markers (particularly CRP > 3 microg/dl); (3) age > 65 years; (4) presence of ST-T wave changes; (5) TIMI Risk Score greater than or equal to 4; (6) diabetes; and/or (7) clinical instability in the setting of suspected NSTE-ACS. Specific clinical, ECG and/or biochemical trigger points modulate the aggressiveness of both the medical therapy and the propensity to perform early angiography with or without subsequent revascularization in patients with NSTE-ACS. Although additional refinements and changes in ACS management are still to come, evidence-based strategies suggest that prompt mechanical revascularization is associated with the best possible clinical outcomes, particularly for patients with high-risk features and in whom benefits of adjunctive, pharmacoinvasive antithrombotic therapies can be consolidated. Patient transfer for cardiac catheterization/percutaneous coronary intervention (PCI) is strongly recommended in patients who manifest high-risk features and/or aggressive treatment trigger criteria, so that this high-risk subgroup may receive definitive, interventional and/or cardiology-directed specialty care at appropriate sites of care. When available, interventional management is preferred in these patients. The importance of safe and effective anticoagulation in the spectrum of management strategies has been confirmed, and the evidence in support of enoxaparin and other antithrombotic agents has been reviewed. Dosing recommendations for enoxaparin use in the setting of PCI have been issued by the CATH Panel and have been summarized in this consensus report. Similar recommendations have been presented for the use of oral antiplatelet agents and GP IIb/IIIa antagonists. The addition of statins, ACE-inhibitors and beta-blockers is also stressed as part of a comprehensive secondary cardioprotective strategy for patients with coronary heart disease.
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PMID:Strategies for optimizing outcomes in the NSTE-ACS patient The CATH (cardiac catheterization and antithrombotic therapy in the hospital) Clinical Consensus Panel Report. 1719 14

The Clinical Trials described in this article were presented at the Hotline and Clinical Trial Update Sessions of the European Society of Cardiology Congress held in September 2007 in Vienna, Austria. The sessions chosen for this article represent the scope of interest of Cardiovascular Drugs and Therapy. The presentations should be considered preliminary, as further analyses could alter the final publication of the results of these studies. PROSPECT evaluated echocardiographic criteria for optimal selection of patients with moderate to severe heart failure who may benefit from cardiac resynchronisation therapy, however concluded that no single echocardiographic measure can be recommended. EVEREST found that tolvaptan, a vasopressin V(2) antagonist, resulted in early weight reduction and improvement of dyspnoea in patients with acute heart failure, but lacked long term improvement. In ARISE, the anti-oxidant succinobucal did not affect the primary outcome in high risk cardiovascular patients, but improved the combination of cardiovascular death, myocardial infarction and stroke, and diabetic control in diabetics. ALOFT showed that the addition of the renin inhibitor aliskiren to an ACE inhibitor or ARB and a beta-blocker leads to favourable effects on neurohormonal actions in heart failure. FINESSE markedly improved coronary patency before PCI with half-dose reteplase/abciximab in STEMI patients, however without significantly improving short-term outcome. The Prague-8 Study evaluated whether routine clopidogrel administered >6 h pre-angiography would be a safe way to achieve therapeutic drug levels in case a follow-up intervention would be considered immediately, but appeared not justified because of bleeding complications. CARESS in MI showed that high risk patients with evolving STEMI who undergo thrombolytic therapy should undergo PCI early after the thrombolysis. Finally, the ACUITY trial found that in moderate or high risk Non ST elevation ACS patients triaged to PCI, coronary artery bypass graft (CABG) surgery, or medical management, bivalirudin, with or without associated GPIIb/IIIa inhibitor therapy, resulted in a marked reduction of bleeding at 30 days whilst preserving the ischemic and mortality benefit at 1 year follow up.
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PMID:Clinical trials update from the European Society of Cardiology Congress in Vienna, 2007: PROSPECT, EVEREST, ARISE, ALOFT, FINESSE, Prague-8, CARESS in MI and ACUITY. 1799 67

Risk stratification is crucial in guiding the acute management of non-ST-segment elevation (NSTE) acute coronary syndromes (ACS). An early invasive strategy (catheterization/revascularization) in conjunction with aggressive antiplatelet and anticoagulant therapy offers the most effective means of reducing ischemic complications in intermediate- and high-risk patients. In low-risk patients, stress testing serves to indicate whether a secondary prevention strategy or elective catheterization/percutaneous coronary intervention and GP IIb/IIIa inhibition is more appropriate. NSTE ACS also confers a long-term risk of recurrent cardiovascular events, regardless of whether initial management follows a medical or interventional approach. Combination aspirin and clopidogrel therapy is effective for secondary prevention across the spectrum of NSTE ACS patients, regardless of risk or initial treatment strategy (conservative or invasive). Long-term aspirin and clopidogrel therapy addresses the thrombotic component of atherothrombosis, while combined beta-blocker, ACE inhibitor, and statin therapy is directed against the atheroma.
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PMID:Risk stratification and the management of non-ST-segment elevation acute coronary syndromes: the role of antiplatelet therapy. 1834 Jan 45


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