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)

PR-39, a proline-arginine-rich angiogenic response peptide, has been implicated in myocardial ischemic reperfusion injury. The present study examined the cardioprotective abilities of PR39 gene therapy. Male C57Bl/J6 mice were randomized to intramyocardial injecton of 10(9) p.f.u. adenovirus encoding PR39 (PR39), FGFR1 dominant negative signaling construct (FGFR1-dn), empty vector (EV), or PR39 adenovirus plus 4 microg of plasmid endcoding a HIF1alpha dominant negative construct (PR39 + HIF1alpha-dn). Seven days later, hearts were subjected to 20 min of ischemia (I) and 2 h. reperfusion (R) ex vivo and aortic and coronary flow, left ventricular developed pressure (LVDP), and LVdp/dt were measured. Myocardial infarct (MI) size and cardiomyocyte apoptosis were measured by TTC staining and TUNEL, respectively. PR39 expression was robust up to 14 days after gene transfer and was absent after EV and FGFR1-dn. Hemodynamics showed no differences at baseline, and heart rate remained unchanged in all groups throughout the experiment. After I-R, hemodynamics remained unchanged in PR39 hearts, but deteriorated significantly in the other groups, except for aortic flow, which remained significantly higher in FGFR1-dn than in EV and PR39 + HIF1alpha-dn (p < 0.05), although it was lower than in PR39 (p < 0.05). MI was 8.7 +/- 0.9 % in PR39, 23.8 +/- 1.1% in FGFR1-dn, 29.9 +/- 2.2% in EV, and 30.8 +/- 2.7 % in PR39 + HIF1alpha-dn (PR39 vs. other groups: p < 0.05; FGFR1-dn vs. EV and PR39 + HIF1alpha-dn: p < 0.05). In PR39, HIF-1alpha protein was higher than in FGFR1-dn and EV. Importantly, cotransfection of HIF1alpha-dn with PR39 completely abolished cardioprotection by PR39. Cardioprotection by PR39 is likely conveyed by protective metabolic and survival responses through HIF1-alpha stabilization and not by angiogenesis, because baseline coronary flow was the same in all groups. Abrogation of FGFR1 signaling conveyed an intermediate degree of cardioprotection.
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PMID:Protection against myocardial ischemia-reperfusion injury by the angiogenic Masterswitch protein PR 39 gene therapy: the roles of HIF1alpha stabilization and FGFR1 signaling. 2223 45

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.
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PMID:Comparison of left ventricular ejection fraction and exercise capacity as predictors of two- and five-year mortality following acute myocardial infarction. 1729 79

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.
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PMID:Survival pathways in hypertrophy and heart failure: the gp130-STAT3 axis. 1791 16

Establishment of functional and stable collaterals in the ischemic myocardium is crucial to restoring cardiac function after myocardial infarction. Here, we show that only dual delivery of a combination of angiogenic and arteriogenic factors to the ischemic myocardium could significantly reestablish stable collateral networks and improve myocardial perfusion and function. A combination of FGF-2 with PDGF-BB, two factors primarily targeting endothelial cells and vascular smooth muscle cells, remarkably promotes myocardial collateral growth and stabilizes the newly formed collateral networks, which significantly restore myocardial perfusion and function. Using various members of the PDGF family together with FGF-2 in an angiogenesis assay, we demonstrate that PDGFR-alpha is mainly involved in angiogenic synergism, whereas PDGFR-beta mediates vessel stability signals. Our findings provide conceptual guidelines for the clinical development of proangiogenic/arteriogenic factors for the treatment of ischemic heart disease.
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PMID:Combinatorial protein therapy of angiogenic and arteriogenic factors remarkably improves collaterogenesis and cardiac function in pigs. 1763 33

Aldosterone concentrations are inappropriately high in many patients with hypertension, as well as in an increasing number of individuals with metabolic syndrome and sleep apnoea. A growing body of evidence suggests that aldosterone and/or activation of the MR (mineralocorticoid receptor) contributes to cardiovascular remodelling and renal injury in these conditions. In addition to causing sodium retention and increased blood pressure, MR activation induces oxidative stress, endothelial dysfunction, inflammation and subsequent fibrosis. The MR may be activated by aldosterone and cortisol or via transactivation by the AT(1) (angiotenin II type 1) receptor through a mechanism involving the EGFR (epidermal growth factor receptor) and MAPK (mitogen-activated protein kinase) pathway. In addition, aldosterone can generate rapid non-genomic effects in the heart and vasculature. MR antagonism reduces mortality in patients with CHF (congestive heart failure) and following myocardial infarction. MR antagonism improves endothelial function in patients with CHF, reduces circulating biomarkers of cardiac fibrosis in CHF or following myocardial infarction, reduces blood pressure in resistant hypertension and decreases albuminuria in hypertensive and diabetic patients. In contrast, whereas adrenalectomy improves glucose homoeostasis in hyperaldosteronism, MR antagonism may worsen glucose homoeostasis and impairs endothelial function in diabetes, suggesting a possible detrimental effect of aldosterone via non-genomic pathways.
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PMID:Aldosterone and end-organ damage. 1768 82

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.
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PMID:Survival pathways in hypertrophy and heart failure: the gp130-STAT axis. 1753 Mar 15

IL-6-type cytokines bind to plasma membrane receptor complexes containing the common signal transducing receptor chain gp130 that is ubiquitously expressed in most tissues including the heart. The two major signalling cascades activated by the gp130 receptor, SHP2/ERK and STAT pathways, have been demonstrated to play important roles in cardiac development, hypertrophy, protection and remodelling in response to physiological and pathophysiological stimuli. Experimental data, both in vivo and in vitro, imply beneficial effects of gp130 signalling on cardiomyocytes in terms of growth and survival. In contrast, it has been reported that elevated serum levels of IL-6 cytokines and gp130 proteins are strong prognostic markers for morbidity and mortality in patients with heart failure or after myocardial infarction. Moreover, it has been shown that the local gp130 receptor system is altered in failing human hearts. In the present review, we summarize the basic principles of gp130 signalling, which requires simultaneous activation of STAT and ERK pathways under the tight control of positive and negative intracellular signalling modulators to provide a balanced biological outcome. Furthermore, we highlight the key role of the gp130 receptor and its major downstream effectors in the heart in terms of development and regeneration and in response to various physiological and pathophysiological stress situations. Finally, we comment on tissue-specific diversity and challenges in targeted pharmacological interference with components of the gp130 receptor system.
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PMID:Role of gp130-mediated signalling pathways in the heart and its impact on potential therapeutic aspects. 1824 92

Meta-analyses showed that exercise training decreased mortality in patients after myocardial infarction, but no single adequately powered trial has shown this benefit. The purpose of this study was to evaluate the effect of cardiac rehabilitative exercise training on prognostic variables derived from the exercise tolerance test and whether these changes had an effect on predicted cardiovascular and all-cause mortality using externally validated risk scores. Two hundred ten consecutive patients who completed a 12-week cardiac rehabilitation program were analyzed. Peak MET level, heart rate recovery, chronotropic index, Duke prognostic score, and Cleveland Clinic Foundation risk score obtained at program entry and exit were compared. All prognostic variables and risk score-derived predicted 5-year mortality rates improved significantly after cardiac rehabilitation. Exercise capacity increased by 32% (6.6 +/- 2.7 to 8.7 +/- 2.9 METS; p <0.0001), heart rate recovery increased by 20% (15 +/- 9 to 18 +/- 10 beats/min; p <0.0001), and chronotropic index increased by 11% (56 +/- 22% to 62 +/- 22%; p <0.0001). Duke prognostic score 5-year predicted cardiovascular mortality rate decreased by 33% (6 +/- 4% to 4 +/- 2%; p <0.0001), and Cleveland Clinic Foundation risk score 5-year predicted total mortality rate decreased by 40% (5 +/- 7% to 3 +/- 5%; p <0.0001). These improvements remained significant in high-risk subgroups. When controlled for age, gender, diabetes, MET level achieved, ejection fraction, and beta-blocker use, changes remained significant (p <0.0001) for each outcome measure. In conclusion, exercise training in supervised cardiac rehabilitation programs significantly improved exercise capacity, measures of chronotropic dynamics, and prognostic risk scores. These differences translate into a decrease in predicted mortality.
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PMID:Effect of exercise training in supervised cardiac rehabilitation programs on prognostic variables from the exercise tolerance test. 1847 49

Myocardial infarction (MI) and the subsequent heart failure remain one of the leading causes of morbidity and mortality world wide. A number of studies have demonstrated that bioderived materials improve cardiac function after implantation because of their angiogenic potential. In this study, we hypothesized that injection of biomaterials into infarcted myocardium can preserve left ventricular (LV) function through its prevention of paradoxical systolic bulging. To test this hypothesis, infarction was induced in rabbit myocardium by coronary artery ligation. After 1 week, 200-microL alpha-cyclodextrin (alpha-CD)/MPEG-PCL-MPEG hydrogel was injected into the infarcted myocardium. Injection of phosphate buffered saline (PBS) served as controls. Twenty-eight days after the treatment, histological analysis indicated that the injection of hydrogel prevented scar expansion and wall thinning compared with the control (p < 0.05) without more microvessel density in infarcted myocardium (p = 0.70). LV ejection fraction, determined by echocardiography, was significantly greater in the hydrogel-treated group (56.09% +/- 8.42%) than the control group (37.26% +/- 6.36%, p = 0.001). The LV end-diastolic and end-systolic diameters were 2.07 +/- 0.33 cm and 1.74 +/- 0.30 cm, respectively, in the control group. Smaller LV end-diastolic diameter (1.61 +/- 0.26 cm, p = 0.005) and smaller end-systolic diameter (1.17 +/- 0.23 cm, p = 0.001) were found in the hydrogel-treated group. These results suggest that alpha-CD/MPEG-PCL-MPEG hydrogel could serve as an injectable biomaterial that prevents LV remodeling and dilation for the treatment of MI.
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PMID:Injection of a novel synthetic hydrogel preserves left ventricle function after myocardial infarction. 1854 87

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.
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PMID:MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets. 1875 67


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