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)

Platelet-derived growth factor (PDGF)-D is a member of the PDGF/vascular endothelial growth factor family that activates PDGF receptor beta (PDGFR-beta). We show that PDGF-D is highly expressed in the myocardium throughout development and adulthood, as well as by arterial vascular smooth muscle cells (vSMCs). To obtain further knowledge regarding the in vivo response to PDGF-D, we generated transgenic mice overexpressing the active core domain of PDGF-D in the heart. Transgenic PDGF-D stimulates proliferation of cardiac interstitial fibroblasts and arterial vSMCs. This results in cardiac fibrosis followed by dilated cardiomyopathy and subsequent cardiac failure. Transgenic mice also display vascular remodeling, including dilation of vessels, increased density of SMC-coated vessels, and proliferation of vSMCs, leading to a thickening of tunica media. The thickening of arterial walls is a unique feature of PDGF-D, because this is not seen when PDGF-C is overexpressed in the heart. These results show that PDGF-D, via PDGFR-beta signaling, is a potent modulator of both vascular and connective tissue growth and may provide both paracrine and autocrine stimulation of PDGFR-beta. Our data raise the possibility that this growth factor may be involved in cardiac fibrosis and atherosclerosis.
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PMID:Platelet-derived growth factor D induces cardiac fibrosis and proliferation of vascular smooth muscle cells in heart-specific transgenic mice. 1622 65

Beta-blockers have been considered for decades as effective agents in preventing coronary events in hypertensive patients. Actually, the scrutiny of the available data arises some doubts over the real value of this pharmacological class. In primary prevention, the clinical benefits of beta-blockers are poorly documented: the studies conducted against placebo (MRC, IPPPSH...) did not show any significant differences regarding the rate of coronary events (except within non smokers); moreover, the beneficial effect of propranolol in preventing sudden deaths and silent myocardial infarctions has been reported byjust one retrospective analysis. Likewise in HAPPHY study, the comparison with diuretics did not emphasize a clear superiority of one of both classes; the better effect of metoprolol regarding overall mortality and fatal coronary events was shown in the pecular subset MAPHY, only. Furthermore, in elderly people, HEP, MRC OA and STOP studies did not find any significant effect of beta-blockers in preventing coronary events, as compared with placebo. However, SHEP study, which involved patients older than 60 years with isolated systolic hypertension receiving first a diuretic, then a beta-blocker(atenolol) in 1/4 of the cases, demonstrated a significant reduction versus placebo both in strokes and in coronary events. Finally, in UKPDS, CAPP, LIFE and CONVINCE studies, atenolol turned out to have a similar efficacy as captopril, losartan and verapamil, in preventing ischemic heart disease. Among the numerous published meta-analyses, that of Psaty pointed out the absence of a primary cardioprotective effect by beta-blockers; more recently, that of Carlberg, emphasized atenolol given alone as the first-line drug to fail in significantly reducing coronary events and strokes. In secondary prevention, some more convincing data may be found in the literature, regarding post myocardial infarction patients (meta-analyses of Staessen, 1982, Yusuf, 1985 and Soriano, 1997), as well as those with stable angina (BIP study in diabetics) or silent ischemia (ASIST study: significant reduction in number and duration of ischemic events by atenolol). Moreover, INVEST study recently showed atenolol and verapamil to have an equivalent efficacy in the hypertensive patients with stable coronary artery disease. Last, hypertension should be reminded as resulting in many cases of heart failure, a pathology where beta-blockers have clearly demonstrated their beneficial effects.
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PMID:[Do beta-blockers prevent coronary events in hypertensive patients?]. 1623 74

Oleylethanolamide (OEA) is a natural fatty acid ethanolamide produced in the heart, but its biological actions in myocardium have not yet been defined. This study was carried out to determine whether OEA could be used to prevent the development of heart failure or improve evolving heart failure. We studied in vivo and in vitro actions of OEA in cardiac muscle. In an animal model of doxorubicin cardiomyopathy, OEA showed robust effects and attenuated the progression of systolic/diastolic dysfunction and ventricular remodeling. During evolving doxorubicin cardiomyopathy, a therapeutic course of OEA treatment partially restored myocardial function. The preventive and therapeutic effects of OEA were associated with significant improvement of survival. To investigate the mechanism of OEA action in cardiac muscle, we have carried out in vitro experiments in cultured cardiomyocytes. The results showed that OEA, through activation of Ras-Raf-1-Mek-Erk signaling, inhibited doxorubicin-induced apoptosis. Additional experiments showed that OEA activation of the Erk pathway involved activation of Neu/ErbB2 receptor, which suggests OEA actions in cardiac muscle might require activation of Neu/ErbB2. In summary, OEA improved ventricular remodeling and augmented cardiac function in doxorubicin cardiomyopathy, possibly involving activation of Neu/ErbB2 and Ras-Erk signaling. These findings suggest OEA is a novel cardioprotective compound that may be used to develop new strategies for the management of cardiomyopathy.
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PMID:Oleylethanolamide activates Ras-Erk pathway and improves myocardial function in doxorubicin-induced heart failure. 1626 55

Three major MAP kinase signaling cascades, ERK, p38, and JNK, play significant roles in the development of cardiac hypertrophy and heart failure in response to external stress and neural/hormonal stimuli. To study the specific function of each MAP kinase branch in adult heart, we have generated three transgenic mouse models with cardiac-specific and temporally regulated expression of activated mutants of Ras, MAP kinase kinase (MKK)3, and MKK7, which are selective upstream activators for ERK, p38, and JNK, respectively. Gene expression profiles in transgenic adult hearts were determined using cDNA microarrays at both early (4-7 days) and late (2-4 wk) time points following transgene induction. From this study, we revealed common changes in gene expression among the three models, particularly involving extracellular matrix remodeling. However, distinct expression patterns characteristic for each pathway were also identified in cell signaling, growth, and physiology. In addition, genes with dynamic expression differences between early vs. late stages illustrated primary vs. secondary changes on MAP kinase activation in adult hearts. These results provide an overview to both short-term and long-term effects of MAP kinase activation in heart and support some common as well as unique roles for each MAP kinase cascade in the development of heart failure.
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PMID:Distinct gene expression profiles in adult mouse heart following targeted MAP kinase activation. 1636 75

Circulating apoptotic proteins are increased in patients with heart failure. We evaluated whether circulating soluble (s) apoptosis-related proteins and inflammation markers are increased in long-term disease free breast cancer survivors and associated with cardiotoxicity, and if subgroups could be identified based on the applied treatments. Circulating tumour necrosis factor (TNF) alpha, sTNF-receptor (sTNF-R) 1 and 2, sFas, sFas ligand, sTNF-related apoptosis inducing ligand (sTRAIL) and serum HER2 were measured with immunoassay. High-sensitivity C-reactive protein (HS-CRP), fibrinogen, plasma B-type and N-terminal atrial natriuretic peptide (NT-ANP and BNP) were also determined. Thirty-four patients with median 6.0 years follow-up and 12 healthy age-matched women were enrolled. Chemotherapy, consisting of five cycles fluorouracil, epirubicin (90 mg/m(2)), cyclophosphamide (FEC) (n=14) or four cycles FEC followed by myeloablation with high-dose carboplatin, cyclophosphamide, thiotepa (n=20), preceded irradiation and tamoxifen. Circulating apoptosis markers were higher in patients than in controls. No associations with cardiac dysfunction were observed. sFas ligand and sTRAIL were higher in the high-dose than in the standard-dose group. In conclusion, we observed increased circulating apoptotic protein levels in long-term disease-free breast cancer survivors, treated with adjuvant chemoradiotherapy, particularly after myeloablative chemotherapy. The potential relation with late cardiotoxicity of antineoplastic therapy deserves further study.
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PMID:Circulating apoptotic proteins are increased in long-term disease-free breast cancer survivors. 1654 63

Recently cardiac transplantation has an important place in treatment of end-stage cardiac failure. In Turkey between 2003 and 2005 at 10 centers 64 cardiac transplantations were performed including five at our facility. Herein we have presented our results. All patients were men of mean age 34.2 +/- 10.7 (17 to 44) years. Upon preoperative echocardiography their mean ejection fraction was 18% +/- 3.27% (17% to 23%). Pulmonary vascular resistance was 4.47 wood unit in one patient and in one case, there was Rh incompatibility between donor and recipient. We used HTK solution for protection of donor hearts. Mean ischemia time was 251.2 +/- 62.7 minutes (155 to 314). Mean aortic clamping time was 84 +/- 4.7 minutes (80 to 90). In all patients we performed a biatrial anastomosis technique. Hemofiltration was used to prevent hemodilution during operation. In the postoperative period four patients had acute renal dysfunction; one, a minor cerebrovascular accident; two, reoperated because of bleeding; one, cholestasis; one, temporary atrio-ventricular block; and one, mediastinitis. Mean follow-up time was 15.6 +/- 19.7 months (2 to 50). Neither early nor late mortality has occurred. All patients are in New York Heart Association class I. In all cases we used triple immunosuppressive therapy. In the follow-up period the mean number of cardiac biopsies per patient was 4.2 +/- 3.03 (2 to 8). Two cases had cardiac catheterization. As a complication of cardiac biopsy, pericardial tamponade developed in one patient; in another one we observed a right ventricular aneursym after cardiac biopsy. Cardiac transplantation was performed with low mortality and morbidity rates in end-stage cardiac failure patients with longer life expectancy and higher life quality. Unfortunately in our country, because of difficulties to find donor hearts, cardiac transplantations were small in number. For better results, we need a larger series.
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PMID:Our experience in cardiac transplantation in Baskent University. 1654 93

Adrenomedullin (AM) is a potent, long-lasting vasoactive peptide originally isolated from human pheochromocytoma. Since its discovery, serum and tissue AM expression have been shown to be increased in experimental models and in patients with cardiac hypertrophy, myocardial infarction and end-stage heart failure with several beneficial effects. Considerable evidence exists for a wide range of autocrine, paracrine and endocrine mechanisms for AM which include vasodilatory, anti-apoptotic, angiogenic, anti-fibrotic, natriuretic, diuretic and positive inotropic. Thus, through regulation of body fluid or direct cardiac mechanisms, AM has additive and beneficial effects in the context of heart disease. Notable molecular mechanisms of AM include cyclic adenosine monophosphate, guanosine-3',5'-monophosphate, PI3K/Akt and MAPK-ERK-mediated cascades. Given the endogenous and multifunctional nature of AM, we consider this molecule to have great potential in the treatment of cardiovascular diseases. In agreement, early experimental and preliminary clinical studies suggest that AM is a new and promising therapy for cardiovascular diseases.
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PMID:Adrenomedullin: molecular mechanisms and its role in cardiac disease. 1658 14

Thrombin activates protease-activated receptor-1 (PAR-1) and engages signaling pathways that influence the growth and survival of cardiomyocytes as well as extracellular matrix remodeling by cardiac fibroblasts. This study examines the role of Shc proteins in PAR-1-dependent signaling pathways that influence ventricular remodeling. We show that thrombin increases p46Shc/p52Shc phosphorylation at Tyr(239)/Tyr(240) and Tyr(317) (and p66Shc-Ser(36) phosphorylation) via a pertussis toxin-insensitive epidermal growth factor receptor (EGFR) transactivation pathway in cardiac fibroblasts; p66Shc-Ser(36) phosphorylation is via a MEK-dependent mechanism. In contrast, cardiac fibroblasts express beta(2)-adrenergic receptors that activate ERK through a pertussis toxin-sensitive EGFR transactivation pathway that does not involve Shc isoforms or lead to p66Shc-Ser(36) phosphorylation. In cardiomyocytes, thrombin triggers MEK-dependent p66Shc-Ser(36) phosphorylation, but this is not via EGFR transactivation (or associated with Shc-Tyr(239)/Tyr(240) and/or Tyr(317) phosphorylation). Importantly, p66Shc protein expression is detected in neonatal, but not adult, cardiomyocytes; p66Shc expression is induced (via a mechanism that requires protein kinase C and MEK activity) by Pasteurella multocida toxin, a Galpha(q) agonist that promotes cardiomyocyte hypertrophy. These results identify novel regulation of individual Shc isoforms in receptor-dependent pathways leading to cardiac hypertrophy and the transition to heart failure. The observations that p66Shc expression is induced by a Galpha(q) agonist and that PAR-1 activation leads to p66Shc-Ser(36) phosphorylation identifies p66Shc as a novel candidate hypertrophy-induced mediator of cardiomyocyte apoptosis and heart failure.
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PMID:Distinct signaling functions for Shc isoforms in the heart. 1669 71

The biological limitations to cardiac regenerative growth create a clinical need to promote more efficient cardiac repair. Experimental studies and early-phase clinical trials indicate that progenitor cells may be useful as a therapeutic tool to improve heart function after myocardial ischaemia. This paper will summarize experimental studies to determine (1) the mechanisms underlying progenitor cell homing to ischaemic tissue and (2) to define transcription factors involved in endothelial maturation of progenitor cells. Homing seems to be assisted by a proteolytic enzyme, cathepsin L, which degrades the extracellular matrix. In an in vitro assay, a cathepsin inhibitor prevented different progenitor cell populations from passing through a matrigel layer. In vivo, progenitor cells lacking cathepsin L had an impaired capacity to promote neovascularization in ischaemic mouse limbs compared with normal, wild-type cells. Differentiation of progenitor cells towards the endothelial phenotype involves a member of the homeobox gene family, HoxA9. HoxA9 regulates endothelial gene expression (eNOS, KDR, VE-cadherin). Moreover, HoxA9-deficient mice have a severe impairment of neovascularization capacity after ischaemia. In the second part of the paper, we describe clinical studies using bone marrow or the peripheral blood-derived cells for functional recovery of patients with acute and chronic heart failure (TOPCARE-AMI, TOPCARE-CHF). Whereas blood-derived and bone marrow-derived progenitor cells were equally effective in patients with acute myocardial infarction, bone marrow-derived cells were significantly better than blood-derived progenitor cells in patients with chronic ischaemic heart disease.
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PMID:Restoration of cardiac function with progenitor cells. 1701 14

Trastuzumab (Herceptin), currently prescribed for metastatic breast cancer, has recently been shown to be effective as adjuvant therapy in early receptor 2 (HER2)-positive breast cancer. Cardiotoxicity is a serious adverse effect. A decrease in left ventricular ejection fraction (LVEF) occurs in as many as 27% of women treated with trastuzumab when combined with standard chemotherapy. The pathophysiology of this effect, which differs from the cardiotoxicity of anthracyclines, remains poorly understood. While overt heart failure is reversed with standard therapy, the longer-term consequences of asymptomatic declines in LVEF remain unknown. Monitoring 3-monthly for 5-10% changes in LVEF, the criteria for cessation of trastuzumab therapy in the clinical trials, is not possible for the population of women who might benefit from trastuzumab for early breast cancer. Extension of this therapy to an older and less fit population than those enrolled in the trials, with less rigorous cardiac screening, may result in significantly more cardiotoxicity.
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PMID:Monitoring the introduction of new drugs--Herceptin to cardiotoxicity. 1734 85


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