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)

Recently we found that post-infarct remodeling disrupts PI3KAkt signaling triggered by erythropoietin (EPO) but an unknown compensatory mechanism preserves EPO-induced protection against infarction in those hearts. In this study, we examined the possibility that ERK-mediated signaling is the compensatory mechanism affording protection in post-infarct remodeled hearts. Four weeks after coronary ligation in situ (post-MI group, post-MI) or a sham operation (sham group, Sham), hearts were isolated, perfused and subjected to 25-min global ischemia/2-h reperfusion. Infarct size was expressed as a percentage of risk area size (%I/R), from which scarred infarct by coronary ligation was excluded. EPO infusion (5 U/ml) before ischemia reduced %I/R similarly in Sham and post-MI (from 62.0 +/- 5.1 to 39.4 +/- 4.8 in Sham and from 58.6 +/- 6.6 to 36.3 +/- 3.8 in post-MI). PD98059, a MEK1/2 inhibitor, abolished this EPO-induced protection in post-MI (%I/R = 60.7 +/- 4.9) but not in Sham (%I/R = 35.1 +/- 5.4). EPO induced PI3K-dependent phosphorylation of Akt in Sham but not in post-MI. EPO increased phosphorylation levels of ERK1/2 both in Sham and post-MI, but this phosphorylation was diminished by a PI3K inhibitor in Sham but not in post-MI. These results suggest that PI3K-independent activation of ERK compensates the lack of signal input from the PI3K-Akt pathway to achieve EPO-induced protection in the remodeled myocardium.
Basic Res Cardiol 2007 Mar
PMID:Impairment of cardioprotective PI3K-Akt signaling by post-infarct ventricular remodeling is compensated by an ERK-mediated pathway. 1694 59

This study evaluated exercise capacity and left ventricular ejection fraction (LVEF) as predictors of long-term mortality in patients with ST-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention. LVEF is a well-established predictor of mortality in patients with STEMI. Exercise capacity, expressed as milliliters per kilogram per minutes or METs (1 MET = 3.5 ml/kg/min), may also serve as an independent predictor of mortality in this cohort. However, it is unclear whether these variables used together more accurately define mortality risk than either alone. In the Primary Angioplasty in Acute Myocardial Infarction-2 trial, 330 patients with long-term mortality data underwent radionuclide ventriculography at rest and cycle ergometer stress testing 6 weeks after percutaneous coronary intervention for STEMI. We used this database to evaluate the ability of LVEF at rest and exercise capacity to predict 2- and 5-year mortality. Exercise capacity <4 METs was a significant predictor of 5-year mortality (odds ratio [OR] 4.54, p = 0.0016). In contrast, decreased LVEF demonstrated a trend toward higher mortality but was not statistically significant at 2- (OR 2.22, p = 0.22) or 5-year (OR 2.04, p = 0.20) follow-up. When evaluated in combination, there was a statistically significant 2-year mortality risk for those with a decreased LVEF and decreased exercise capacity (OR 6.03, p = 0.018). Exercise capacity was a better predictor of 2- and 5-year mortality than LVEF in patients with STEMI treated with percutaneous intervention. In conclusion, when combined with LVEF, exercise capacity provides independent and additive information regarding long-term prognosis.
Am J Cardiol 2007 Feb 15
PMID:Comparison of left ventricular ejection fraction and exercise capacity as predictors of two- and five-year mortality following acute myocardial infarction. 1729 79

Oxidative stress resulting from increased superoxide generation by NADPH oxidase is implicated in the pathophysiology of human heart failure. Downstream targets of NADPH oxidase remain undefined and available information is restricted to the left ventricle (LV). Thus, we aimed to assess the cascade of events triggered by increased NADPH oxidase activity (lipid peroxidation and activation of mitogen-activated protein kinases ERK1/2, JNK and p38) and their mutual relationship in right (RV) and (LV) of end-stage failing human hearts. When compared to control ventricles, diseased RV and LV showed a significant increase in NADPH oxidase superoxide production that positively correlated with p47(phox) membrane translocation (RV: r=0.76, P<0.001; LV: r=0.79, P<0.001). MDA content, a marker of lipid peroxidation, was also enhanced and ERK and p38, but not JNK, were activated. For all these relevant steps of the oxidative stress pathway, a significant correlation was observed between LV and RV from the same heart (NADPH-dependent superoxide production: r=0.678, P<0.0055; MDA: r=0.95, P<0.0001; p-p38/p38 ratio: r=0.926, P<0.0001; p-ERK/ERK ratio: r=0.913, P<0.0001). We concluded that in human heart failure, both ventricles are targets of NADPH oxidase superoxide generation which in turn may trigger the coordinated activation of downstream signaling components. This pathway may contribute to adverse remodeling of the LV and RV and subsequent progression toward end-stage heart failure, suggestive of new therapeutic targeting strategy.
J Mol Cell Cardiol 2007 Apr
PMID:NADPH oxidase-dependent redox signaling in human heart failure: relationship between the left and right ventricle. 1734 42

The existing literature indicates a crucial role of p38 MAP (mitogen-activated protein) kinase (p38MAPK) and its downstream target MAPKAP kinase 2 (MK2) in ischemic preconditioning (IPC). Accordingly, deletion of MK2 gene should abolish the cardioprotective ability of IPC. Interestingly, we were able to partially precondition the hearts from MK2(-/-) knockout mice suggesting the existence of an as yet unknown alternative downstream target of p38MAPK. A recent study from our laboratory also determined a crucial role of CREB (cyclic AMP response element binding protein) in IPC. Since CREB is a downstream target of MSK-1 (mitogen- and stress-activated protein kinase-1) situated at the crossroad of ERK (extracellular receptor kinase) and p38MAPK signaling pathways, we reasoned that MSK-1 could be a downstream molecular target for p38MAPK and ERK signaling in the IPC hearts. To test this hypothesis, the rat hearts were subjected to IPC by four cyclic episodes of 5 min ischemia and 10 min reperfusion. As expected, IPC induced the activation of ERK1/2, p38MAPK, MK2 and HSP (heat shock protein) 27 as evidenced by their increased phosphorylation; and the inhibition of p38MAPK with SB203580 almost completely, and the inhibition of ERK1/2 with PD098059 partially, abolished cardioprotective effects of IPC. Inhibition of MSK-1 with short hairpin RNA (shRNA) also abolished the IPC-induced cardioprotection. SB203580 partially blocked the effects of MSK-1 suggesting that MSK-1 sits downstream of p38MAPK. shRNA-MSK-1 blocked the contribution of both p38MAPK and ERK1/2 as it is uniquely situated at the downstream crossroad of both of these MAP kinases. Although MSK-1 sits downstream of both ERK1/2 and p38MAPK, ERK1/2 activation appears to play less significant role compared to p38MAPK, since its inhibition blocked MSK activation only partially. Consistent with these results, shRNA-MSK-1 blocked the partial PC in MK2(-/-) hearts, and in combination with SB203580, completely abolished the PC effects in the wild-type hearts. The IPC-induced survival signaling was almost completely inhibited with SB203580, and only partially with PD 098059 as evidenced from the inhibition patterns of IPC induced activation of CREB, Akt and Bcl-2. Again SB203580 alone or in combination with shRNA-MSK-1 inhibited IPC induced survival signal comparatively, suggesting that MSK-1 exists downstream of p38MAPK. Taken together, these results indicate for the first time MSK-1 as an alternative (other than MK2) downstream target for p38MAPK, which also transmits survival signal through the activation of CREB.
J Mol Cell Cardiol 2007 May
PMID:Ischemic preconditioning involves dual cardio-protective axes with p38MAPK as upstream target. 2323 Jun 4

This review discusses the historical aspects, current state of the art, and potential future advances in the areas of nomenclature and databases for congenital heart disease. Five areas will be reviewed: (1) common language = nomenclature, (2) mechanism of data collection (database or registry) with an established uniform core data set, (3) mechanism of evaluating case complexity, (4) mechanism to ensure and verify data completeness and accuracy, and (5) collaboration between medical subspecialties. During the 1990s, both the Society of Thoracic Surgeons (STS) and the European Association for Cardiothoracic Surgery (EACTS) created congenital heart surgery outcomes databases. Beginning in 1998, the EACTS and STS collaborated in the work of the International Congenital Heart Surgery Nomenclature and Database Project. By 2000, a common congenital heart surgery nomenclature, along with a common core minimal data set, were adopted by the EACTS and the STS and published in the Annals of Thoracic Surgery. In 2000, the International Nomenclature Committee for Pediatric and Congenital Heart Disease was established; this committee eventually evolved into the International Society for Nomenclature of Paediatric and Congenital Heart Disease (ISNPCHD). The working component of ISNPCHD is the International Working Group for Mapping and Coding of Nomenclatures for Paediatric and Congenital Heart Disease, also known as the Nomenclature Working Group (NWG). By 2005, the NWG cross-mapped the EACTS-STS nomenclature with the European Paediatric Cardiac Code of the Association for European Paediatric Cardiology and created the International Paediatric and Congenital Cardiac Code (IPCCC) ( http://www.IPCCC.NET ). This common nomenclature (IPCCC), and the common minimum database data set created by the International Congenital Heart Surgery Nomenclature and Database Project, are now utilized by both EACTS and STS; since 1998, this nomenclature and database have been used by both the STS and EACTS to analyze outcomes of more than 75,000 patients. Two major multi-institutional efforts have attempted to measure case complexity; the Risk Adjustment in Congenital Heart Surgery-1 and the Aristotle Complexity Score. Efforts to unify these two scoring systems are in their early stages but are encouraging. Collaborative efforts involving the EACTS and STS are under way to develop mechanisms to verify data completeness and accuracy. Further collaborative efforts are also ongoing between pediatric and congenital heart surgeons and other subspecialties, including pediatric cardiac anesthesiologists (via the Congenital Cardiac Anesthesia Society), pediatric cardiac intensivists (via the Pediatric Cardiac Intensive Care Society), and pediatric cardiologists (via the Joint Council on Congenital Heart Disease). Clearly, methods of congenital heart disease outcomes analysis continue to evolve, with continued advances in five areas: nomenclature, database, complexity adjustment, data verification, and subspecialty collaboration.
Pediatr Cardiol
PMID:Nomenclature and databases - the past, the present, and the future : a primer for the congenital heart surgeon. 1748 90

Circulating levels of interleukin (IL)-6 and related cytokines are elevated in patients with congestive heart failure and after myocardial infarction. Serum IL-6 concentrations are related to decreasing functional status of these patients and provide important prognostic information.Moreover, in the failing human heart, multiple components of the IL-6- glycoprotein (gp)130 receptor system are impaired, implicating an important role of this system in cardiac pathophysiology.Experimental studies have shown that the common receptor subunit of IL-6 cytokines is phosphorylated in response to pressure overload and myocardial infarction and that it subsequently activates at least three different downstream signaling pathways, the signal transducers and activators of transcription 1 and 3 (STAT1/3), the Src-homology tyrosine phosphatase 2 (SHP2)-Ras-ERK, and the PI3K-Akt system. Gp130 receptor mediated signaling promotes cardiomyocyte survival, induces hypertrophy, modulates cardiac extracellular matrix and cardiac function. In this regard, the gp130 receptor system and its main downstream mediator STAT3 play a key role in cardioprotection. This review summarizes the current knowledge of IL-6 cytokines, gp130 receptor and STAT3 signaling in the heart exposed to physiological (aging, pregnancy) and pathophysiological stress (ischemia, pressure overload, inflammation and cardiotoxic agents) with a special focus on the potential role of individual IL-6 cytokines.
Basic Res Cardiol 2007 Jul
PMID:Survival pathways in hypertrophy and heart failure: the gp130-STAT3 axis. 1791 16

Mitogen-activated protein (MAP) kinases have been implicated in hemodynamic load induced heart failure. Both angiotensin II (Ang II) and mechanical stretch activate MAP kinases in cardiac myocytes. In this study, we used a neonatal rat ventricular myocyte (NRVM) model to determine the role of focal-adhesion kinase (FAK) in beta1 integrin mediated MAP kinase activation in response to mechanical stretch in presence and absence of Ang II receptor blockade (ATB). NRVM plated on deformable membranes coated with collagen IV were exposed to 20% equiaxial static-stretch. beta1 integrin signaling was blocked by adenovirus-mediated expression of a dominant-negative form of beta1D integrin (tac-beta1D). FAK signaling was disrupted by infecting NRVM with adenovirus expressing FAK-related non-kinase (FRNK). Western blot analysis was used to assess the phosphorylation of MAP kinases. In the presence and absence of ATB, mechanical stretch caused maximal phosphorylation of ERK, p38 and JNK at 5 min, which was significantly attenuated in NRVM expressing tac-beta1D. In the presence of ATB, FRNK overexpression significantly increased basal phosphorylation of ERK (40.2+/-8.6% P<0.05), p38 (39.5+/-11.7%, P<0.05), JNK (86+/-29.4%, P<0.05) and stretch-induced p38 (48.1+/-8.7%, P<0.05) and JNK (85.0+/-19.4%, P<0.05) phosphorylation. However, in the absence of ATB, FRNK overexpression significantly reduced basal and stretch-induced phosphorylation of only ERK. Examination of FAK activation revealed that beta1 integrin was required for stretch-induced phosphorylation of FAK at Y397 and Y925, but not Y861. In summary, mechanical stretch-activated ERK1/2, p38 and JNK through FAK independent and dependent mechanisms. Beta1 integrin was required for FAK independent activation of all three MAP kinases, whereas cross-talk between beta1 integrin and Ang II receptors mediated FAK dependent regulation of ERK1/2.
J Mol Cell Cardiol 2007 Aug
PMID:Stretch-induced MAP kinase activation in cardiac myocytes: differential regulation through beta1-integrin and focal adhesion kinase. 1758 25

Vascular endothelial growth factor receptors (VEGFRs) are previously considered to exist exclusively in endothelial cells. However, little is known if the receptors are expressed in other non-endothelial cells. In this study, we measured activation of two VEGFRs, Flk-1 and Flt-1, and their biological functions in cultured adventitial fibroblasts and injured rat carotid injury arteries induced by balloon angioplasty. Our results indicated that Flt-1, but not Flk-1, existed in adventitial fibroblasts. Angiotensin II increased Flt-1 protein expression in a time- and concentration-dependent manner. Adventitial fibroblast migration stimulated by vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) required Flt-1 expression. The Flt-1-induced adventitial fibroblast migration was blocked by anti-Flt-1 neutralizing antibody and soluble VEGFR1 protein (sFlt-1). However, Flt-1 activation did not enhance cell proliferation. In addition, Flt-1 expression was significantly increased in the neointima and adventitia in injured rat carotid arteries. We concluded that functional expression of Flt-1 in adventitial fibroblasts might be an important mediator in the pathogenesis of vascular remodeling after arterial injury.
J Mol Cell Cardiol 2007 Sep
PMID:Expression and function of vascular endothelial growth factor receptors (Flt-1 and Flk-1) in vascular adventitial fibroblasts. 1765 52

Vincristine is a chemotherapeutic agent that disrupts microtubules. We noted that paclitaxel (Taxol), which stabilizes microtubules, protected cultured adult mouse cardiac myocytes from oxidative stress induced by H(2)O(2). We hypothesized that vincristine, which disrupts microtubules, should have the opposite effect. To our surprise, we found that pretreatment with concentrations of vincristine ranging from 30 to 120 micromol/L for 60 min preserved myocyte viability and morphology after incubation with 30 micromol/L of H(2)O(2) for 35 min as measured by trypan blue exclusion. The cardioprotective effects of vincristine were also observed during prolonged hypoxia. With continuous exposure to vincristine, survival lasted for as long as 24 h, but longer periods of exposure up to 42 h resulted in extensive cell death. Despite microtubule disruption evidenced on deconvolution microscopy, vincristine activated a prosurvival pathway resulting in increased phosphorylation of Akt, ERK and GSK-3beta and in reduced cytochrome C release into the cytosol. Pharmacological inhibitors of Akt and Erk attenuated the cardioprotective effect of vincristine. We conclude that short-term pretreatment with vincristine exerts dramatic protective effects in cultured adult mouse myocytes subjected to acute oxidative stress. Despite causing microtubule disruption, vincristine initiates a prosurvival signaling pathway. As vincristine and doxorubicin are often used in conjunction to treat patients, it is possible that vincristine could be used to modify the cardiotoxicity of doxorubicin.
J Mol Cell Cardiol 2007 Sep
PMID:Acute vincristine pretreatment protects adult mouse cardiac myocytes from oxidative stress. 1766 2

To investigate the effect of anti-cytokine-based therapy in the course of diabetic cardiomyopathy, we performed a study using an anti-TNF-alpha monoclonal antibody treatment (mab) in Sprague male Dawley (SD) rats with streptozotocin-induced diabetic cardiomyopathy. Five days after streptozotocin injection, rats were treated with the anti-TNF-alpha mAb C432A for 6 weeks.At the end of the study, left ventricular (LV) function was determined by a pressure-catheter. Intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, beta2-lymphocyte-integrins(+) (CD18(+), CD11a(+), CD11b(+)), ED1/CD68(+) and cytokine (TNF-alpha, interleukin (IL)-1beta)- expressing infiltrates, total collagen content and stainings of collagen I and III were quantified by digital image analysis. LV phosphorylated and total ERK protein levels were determined by Western Blot. TNFalpha-antagonism reduced ICAM-1- and VCAM-1 expression and leukocyte infiltration to levels of non-diabetics and decreased macrophage residence by 3.3-fold compared with untreated diabetics. In addition, anti-TNF-alpha mAb-treatment decreased diabetes-induced cardiac TNF-alpha and IL-1beta expression by 2.0-fold and 1.8- fold, respectively, and reduced the ratio of phosphorylated to total ERK by 2.7-fold. The reduction in intramyocardial inflammation was associated with a 5.4-fold and 3.6-fold reduction in cardiac collagen I and III content, respectively. This was reflected by a normalization of cardiac total collagen content to levels of non-diabetics and associated with an improved LV function. TNFalpha-antagonism attenuates the development of experimental diabetic cardiomyopathy associated with a reduction of intramyocardial inflammation and cardiac fibrosis.
Basic Res Cardiol 2007 Nov
PMID:Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy. 1790 96


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