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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac insufficiency represents a major risk factor in patients about to undergo non-cardiac surgery. The post-operative mortality is linked to the severity of the pre-operative functional impairment: rising from 4% in NYHA class 1 to 67% in class IV. The operative risk is greater when the cardiac insufficiency is more disabling, the patient is older (> 70 years) and if there is a history of acute pulmonary oedema and a gallop bruit on auscultation. The use of metabolic equivalents (Duke Activity Status Index) is recommended: the functional capacity is defined as excellent if > 7 MET, moderate between 4 and 7, or poor if < 4. A non-invasive evaluation of left ventricular function is necessary in each patient with obvious congestive cardiac insufficiency or poor control under the American consensus, but it is rare that the patient has not already been seen by a cardiologist. The degree of per-operative haemodynamic constraint is linked to the surgical technique and is stratified according to the type of surgical intervention and whether or not it is performed as an emergency. An intervention duration > 5 hours is associated with an increased peri-operative risk of congestive cardiac insufficiency and non-cardiac death. Deaths from a cardiac cause are thus twice as frequent after intra-abdominal, non-cardiac thoracic or aortic surgery and the post-operative cardiac complications are six times more frequent. Numerous studies have attempted to document the impact of different anaesthetic techniques on the prognosis for the population at increased risk of post-operative cardiovascular complications. It is advisable to opt for peripheral nerve blocks. The cardiovascular morbidity and overall mortality do not differ between general anaesthetic, epidural anaesthetic or spinal nerve block. The ASA (American Society of Anesthesiologists) classification is widely used to determine the overall risk. The ASA class and the age are however too coarse as methods of evaluation for the individual risk and for giving judicious pre-operative advice. Multifactorial cardiac risk indexes such as that of Goldman allow overall evaluation (taking the patient and the intervention into account) of the peri-operative cardiovascular risk in non-cardiac surgery as a function of predictive clinical elements. Nine variables concerning the patient's history, the physical examination and several simple supplementary examinations are identified for which the relative weight is recorded under a points system. The average risk score for a given procedure is converted into an average risk for a given patient using a nomogram such as Detsky's. Surgical acts which do not impose major constraints on the cardiocirculatory apparatus (ophthalmic surgery for example) do not require supplementary examinations. The risk of post-operative cardiac complications is low in the absence of the 9 risk factors defined by Goldman, as is an ischaemic syndrome (angina on light physical activity, unstable angina, myocardial infarction). Certain risk factors (jugular congestion, gallop bruit, recent myocardial infarction, non-sinus rhythm, extrasystoles, aortic stenosis) obviously require appropriate treatment beforehand. The sometimes difficult process demands a dialogue between the cardiologist and the surgeon, the recognition of the risk of surgery in a given centre, and the opinion of the patient duly informed of the terms of the discussion about him.
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PMID:[Evaluation of the cardiac risks in non-cardiac surgery in patients with heart failure]. 1193 51

The enzyme neutral endopeptidase (NEP; EC 3.4.24.11) cleaves several vasoactive peptides such as the atrial natriuretic peptide (ANP). ANP is a hormone of cardiac origin with diuretic and natriuretic actions. Despite elevated circulating levels of ANP, congestive heart failure (CHF) is characterized by progressive sodium and water retention. In order to elucidate the loss of natriuretic and diuretic properties of ANP in CHF we analyzed activity, protein concentrations, mRNA and immunostaining of NEP in kidneys of different models of severe CHF in the rat.CHF was induced by either aortocaval shunt, aortic banding or myocardial infarction in the rat. All models were defined by increased left ventricular end-diastolic pressure and decreased contractility. The diminished effectiveness of ANP was reflected by reduced cGMP/ANP ratio in animals with shunt or infarction. Renal NEP activity was increased in rats with aortocaval shunt (203 +/- 7%, p < 0.001), aortic banding (184 +/- 11%, p < 0.001) and infarction (149 +/- 10%, p < 0.005). Western blot analysis revealed a significant increase in renal NEP protein content in two models of CHF (shunt: 214 +/- 57%, p < 0.05; infarction: 310 +/- 53 %, p < 0.01). The elevated protein expression was paralleled by a threefold increase in renal NEP-mRNA level in the infarction model. The increased renal NEP protein expression and activity may lead to enhanced degradation of ANP and may contribute to the decreased renal response to ANP in heart failure. Thus, the capacity to counteract sodium and water retention, would be diminished. The increased renal NEP activity may therefore be a hitherto unknown factor in the progression of CHF.
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PMID:Increased expression of renal neutral endopeptidase in severe heart failure. 1238 78

Hepatocyte growth factor (HGF) is released in response to myocardial infarction and may play a role in regulating cardiac remodeling. Recently, HGF was found to inhibit the apoptosis of cardiac muscle cells. Because GATA-4 can induce cell survival, the effects of HGF on GATA-4 activity were investigated. Treatment of HL-1 cells or primary adult rat cardiac myocytes with HGF, at concentrations that can be detected in the human serum after myocardial infarction, rapidly enhances GATA-4 DNA-binding activity. The enhanced DNA-binding activity is associated with the phosphorylation of GATA-4. HGF-induced phosphorylation and activation of GATA-4 is abolished by MEK inhibitors or the mutation of the ERK phosphorylation site (S105A), suggesting that HGF activates GATA-4 via MEK-ERK pathway-dependent phosphorylation. HGF enhances the expression of anti-apoptotic Bcl-x(L), and this is blocked by dominant negative mutants of MEK or GATA-4. Forced expression of wild-type GATA-4, but not the GATA-4 mutant (S105A) increases the expression of Bcl-x(L). Furthermore, expression of the GATA-4 mutant (S105A) suppresses HGF-mediated protection of cells against daunorubicin-induced apoptosis. These results demonstrate that HGF protects cardiac muscle cells against apoptosis via a signaling pathway involving MEK/ERK-dependent phosphorylation of GATA-4.
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PMID:Hepatocyte growth factor induces GATA-4 phosphorylation and cell survival in cardiac muscle cells. 1246 31

The aim of this prospective, randomized study was to investigate the effect of pretreatment with two different intracellular calcium-lowering drugs (verapamil and metoprolol) on recovery from atrial effective refractory period (AERP) shortening after internal electrical cardioversion (EC) of persistent atrial fibrillation (AF) in patients on amiodarone. Twenty-one patients on amiodarone for at least 30 days were referred to our hospital for internal EC of a persistent AF refractory to external EC. They were randomized to receive only amiodarone (group AMI, n=7), or amiodarone and verapamil 240 mg/day (group VER, n=7), or amiodarone and metoprolol 100 mg/day (group MET, n=7). Left AERP was measured 10 min and 24 h after EC. AERP was also determined in 13 controls. The AERP after 10 min was significantly shorter in group AMI (201 (31) ms, P<0.02) and group MET (203 (34) ms, P<0.03) than in controls (249 (45) ms), but not in group VER (237 (51) ms, P=NS). The AERP after 24 h was still significantly shorter in group AMI (204 (38) ms, P<0.04) than in controls, but not in group MET (225 (52) ms, P=NS) or in group VER (290 (36) ms, P=NS). Pretreatment with amiodarone and verapamil prevents AERP shortening, while pretreatment with amiodarone and metoprolol only accelerated AERP recovery.
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PMID:Effects of verapamil and metoprolol on recovery from atrial electrical remodeling after cardioversion of long-lasting atrial fibrillation. 1255 36

The Angiotensin I converting enzyme (ACE, EC 3.4.14.1, kininase II) and neutral endopeptidases (NEP, NEP 24.11) are mechanistically related metallopeptidases. They play a key role in the regulation of blood pressure, body fluid homeostasis and cell growth. Therefore, they are implicated in the pathogenesis of arterial hypertension, congestive heart failure, left ventricular remodeling after myocardial infarction and other cardiovascular diseases. Furthermore, since these two metallopeptidases possess some subsite and substrate similarities, as indicated by their interaction with certain mercaptoalkanoyl inhibitors, they are regarded as an important common target for pharmacological inhibition with a single drug. MDL 100240 is a pro-drug that, upon conversion to MDL 100173, acts as a potent dual inhibitor of ACE and NEP with a balanced activity on both enzymes. Only very limited pharmacokinetic studies with MDL 100240 have been published. These studies used a high pressure liquid chromatography method with UV absorbance detection to quantify the drug. According to the studies in dogs the terminal t(1/2) of MDL 100173 was 35.7 h. The area under the curve for total MDL 100173 was nearly 10-fold greater than the sum of the areas under the curve for MDL 100240 and for unconjugated MDL 100173. These results support the hypothesis that MDL 100240 is hydrolyzed in plasma to the active thiol, MDL 100173, which is rapidly conjugated with endogenous plasma thiols thus providing a pathway for elimination. Studies in vivo in experimental models of hypertension and congestive heart failure confirmed the vasodilatory and natriuretic effects of MDL, which appear to be independent of the degree of activation of the renin-angiotensin-aldosterone system. In addition, MDL 100240 showed an impressive effectiveness both in preventing and in regressing hypertension-induced vascular remodeling and cardiac hypertrophy. Accordingly, MDL 100240 is being developed for the treatment of cardiovascular diseases, including hypertension and congestive heart failure. If the promises of this novel therapeutic strategy are fulfilled, clinical trials are expected to demonstrate advantages of MDL 100240 over pure ACE inhibitors.
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PMID:Dual ACE and NEP inhibitors: a review of the pharmacological properties of MDL 100240. 1259 17

Vascular endothelial growth factor (VEGF), produced predominantly by endothelial cells, is involved in angiogenesis and mitogenesis. Myofibroblasts (myoFb) are phenotypically transformed fibroblast-like cells found at the site of myocardial infarction. Since myoFb play a role in tissue repair/remodeling at the site of infarction, and express endothelin and angiotensin II (AngII), it was interesting to investigate whether myoFb express VEGF and its receptors de novo, and if the expression is influenced by vasoactive peptides. Primary cultures of myoFb were isolated from 4-week-old adult rat heart infarct were used in this study. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), utilizing primers designed to amplify known isoforms of VEGF revealed expression of two predominant forms, VEGF120 and VEGF164 and northern blot hybridization detected VEGF mRNA of 4.5 kb. VEGF actions are mediated via two major receptors, Flt-1 and KDR, and hence the expression of these receptors was investigated. Flt-1 and KDR expression in myoFb was detected by RT-PCR, RNA transcripts were confirmed by northern blot hybridization while western blot confirmed the presence of VEGF, Flt-1 and KDR proteins in myoFb. In this study AngII upregulated VEGF and Flt-1 expression in myoFb, but not KDR; this was mediated predominantly by AT1-receptor. We report for the first time that cardiac myoFb, isolated from the site of infarction express VEGF, its receptors, Flt-1 and KDR, with modulation of VEGF and Flt-1 expression by AngII. Thus, VEGF may contribute to tissue remodeling and angiogenesis at the site of infarction in an autocrine manner.
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PMID:Cardiac myofibroblasts: a novel source of vascular endothelial growth factor (VEGF) and its receptors Flt-1 and KDR. 1267 42

In hearts with chronic left ventricular (LV) systolic dysfunction secondary to hypertension or myocardial infarction, MAPK phosphorylation and/or activity are increased. Whether other settings of LV dysfunction not associated with ischemia-reperfusion are also characterized by increased MAPK phosphorylation or activity is unknown. After 3 wk of rapid LV pacing (400 beats/min), eight rabbits displayed clinical signs of heart failure (HF), and echocardiography revealed an increase in LV end-diastolic diameter from 15.6 +/- 0.7 (means +/- SE) to 18.8 +/- 0.7 mm and a reduced shortening fraction from 31 +/- 1to10 +/- 2% (both P < 0.05). Morphological alterations in HF included increased numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cardiomyocytes, extent of fibrosis, and cross-sectional cardiomyocyte area. Total p38 MAPK did not differ between failing and normal hearts (n = 8). However, p38 MAPK phosphorylation [164,488 +/- 29,323 vs. 43,565 +/- 14,817 arbitrary units (AU), P < 0.05, densitometry] and the activities of p38 MAPK-alpha and -beta were increased in failing compared with normal hearts (149,441 +/- 38,381 and 170,430 +/- 32,952 vs. 68,815 +/- 28,984 and 81,788 +/- 22,774 AU, respectively, both P < 0.05). In failing compared with normal hearts, total and phosphorylated JNK46 and JNK54 MAPK were increased, whereas total and phosphorylated ERK MAPK remained unchanged. In pacing-induced HF, p38 and JNK MAPK phosphorylation as well as p38 MAPK activity was increased. Further studies will have to define whether or not chronic specific blockade of MAPK activity can interfere with apoptosis/fibrosis and thereby attenuate the progression of HF.
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PMID:Stress kinase phosphorylation is increased in pacing-induced heart failure in rabbits. 1284 18

Cardiac hypertrophy is an adaptive response to a number of heart diseases including myocardial infarction. Although it can be compensatory at first, sustained hypertrophy is often a transition to heart failure. We have found that cardiomyocytes in culture can survive mild doses of H2O2 but develop hypertrophy involving activation of p70 S6 kinase 1 (p70S6K1). Here, the role of p42/p44(ERK) and p38 MAPK in oxidant-induced hypertrophy is tested. H2O2- induced phosphorylation (activation) of p42/p44(ERK) and p38 within 10 min of 200 microM H2O2 exposure. Although p42/p44(ERK) remained highly phosphorylated from 60 to 120 min, the level of p38 phosphorylation reached highest at 60 min and started to decline at 90 min. Inhibiting ERKs with PD98059 attenuated H2O2-induced AP-1 activation but did not affect H2O2-induced p70S6K1 activation or cardiomyocyte enlargement as measured by increases in cell volume and protein content. In contrast, the p38 inhibitor SB202190 has no inhibitory effect on AP-1 activation but partially prevented H2O2 from inducing p70S6K1 activation and cell enlargement. These data suggest that while p42/p44(ERK) participates in gene expression associated with hypertrophy, p38 may regulate cell size increase by p70S6K1 activation.
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PMID:Distinct roles of p42/p44(ERK) and p38 MAPK in oxidant-induced AP-1 activation and cardiomyocyte hypertrophy. 1450 Oct 30

Data on the functional status of the cardiorespiratory system are required to identify patients at risk for postoperative complication in the presence of lung diseases. Very many factors influence the course of an operation and the postoperative period so there is no golden standard or the only parameter for predicting how the postoperative period runs. Patients with normal spirographic values (FEV1, more than 80%??) and without cardiovascular comorbidity are at a slight risk for postoperative complications. These patients do not need to be additionally examined. A less than one-month history of myocardial infarction, instable angina pectoris, decompensated heart failure, severe valvular disease are contraindications to planned surgery. The risk of cardiovascular events is high when the signs of myocardial ischemia occur with low exercise (less than 4 MET). Stress echocardiography, loading tests, and radioisotopic study are used as auxiliary techniques, FEV1, under 60%; ppo-FEV1, and ppo-DC, under 40%; VO2max, under 15 ml/kg/min are the values of a high risk for respiratory complications.
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PMID:[Functional studies in the prediction of postoperative complications in the presence of lung diseases]. 1452 92

Apoptosis is involved in ventricular remodeling after myocardial infarction (MI). We investigated the effects of the vasopeptidase inhibitor (VPI) omapatrilat on cardiomyocyte apoptosis and compared it to the angiotensin converting enzyme inhibitor (ACEI) captopril in the rat post-MI model and in cultured neonatal rat cardiomyocytes. Wistar males rats surviving 4 h post-MI were assigned to omapatrilat (40 or 80 mg/kg/day), captopril (160 mg/kg/day) or no treatment. After 56 days, hemodynamic measurements were performed (n = 96) and rats were sacrificed. One group had assessment of cardiac remodeling and detection of DNA fragments by in situ end labelling method (ISEL), while the other had morphologic measurements and DNA laddering assessed. In addition, cultured neonatal rat cardiomyocytes (n = 6) were treated for 72 h with vehicle, captopril or omapatrilat in the presence or absence of the apoptosis inducing agent H2O2. Omapatrilat and captopril resulted in similar improvements of hemodynamic measurements, ventricular weight and dilatation, cardiac fibrosis and myocardial cell cross-section in large MI rats. Omapatrilat increased scar thickness more than did captopril. All sham-operated groups had little evidence of apoptosis. In the large MI group, there was a significant increase in ISEL-positive cells in the control (0.095 +/- 0.016%) and captopril (0.124 +/- 0.024%) groups in comparison with control sham-operated (0.006 +/- 0.006%), but this increase was limited to the peri-MI area. Omapatrilat (0.012 +/- 0.012% for both doses) prevented the increase in apoptosis in the peri-MI area. Also, omapatrilat but not captopril reduced DNA laddering in large MI. Moreover, in cultured neonatal rat cardiomyocytes, omapatrilat but not captopril reduced apoptosis as assessed by DNA laddering. The VPI omapatrilat, with its combination of NEP and ACE inhibition, suppresses cardiomyocyte apoptosis post-MI and in neonatal cultured rat cardiomyocytes more than the ACEI captopril, but this does not result in significant hemodynamic or morphologic differences between omapatrilat and captopril.
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PMID:Comparative effects of a vasopeptidase inhibitor vs. an angiotensin converting enzyme inhibitor on cardiomyocyte apoptosis in rats with heart failure. 1467 3


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