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)

Endothelial dysfunction, a well recognized marker of cardiovascular risk, is an early event in arteriosclerosis process. Diabetes mellitus, hypertension and dyslipidemia, known risk factors for coronary disease have been associated with endothelial dysfunction, which improves after the control of these factors. Statins have additional benefits on endothelial function not related to decreasing cholesterol levels, known as pleiotropic effects. Most recently it has been reported the effect of statins promoting bone marrow-derived mononuclear cells. These cells are positive for CD34 and KDR superficial markers of endothelial cellular lineage, which is consistent with the hypothesis that they constitute the endothelial progenitor cells. Circulating endothelial progenitor cells are involved in the repair process of the endothelium after endothelial-cell injury in myocardial ischemia, angina and other stressful situations. Recent studies have demonstrated an inverse relationship between the EPC count in peripheral blood and risk of developing a cardiovascular event. In addition, circulating EPC correlates with the presence of endothelial dysfunction and could play a role as a surrogate biologic marker in vascular function. The effect of statins on endothelial progenitor cells might contribute to improve endothelial function leading to a decrease in vascular risk, independently of their impact on LDL cholesterol. In this paper, we review the role of statins in EPC mobilization, its effect in endothelial function restoration and the relevance of this finding in cardiovascular risk. We also review future therapeutic implications.
Cardiovasc Hematol Agents Med Chem 2007 Oct
PMID:The role of endothelial progenitor cells and statins in endothelial function: a review. 1797 88

Whereas fibroblast growth factors (FGFs) classically transmit their signals via high-affinity tyrosine kinase receptors (FGFR1-4), recent evidence strongly implicates non-tyrosine kinase receptors (NTKR) or cell-surface FGFR-interacting proteins as important players in FGF signalling. Although NTKR have lower affinity for FGFs in comparison with cognate tyrosine kinase receptors, because of their high abundance they can effectively bind FGFs and produce unique biological effects independent of FGFRs. A prime example of such NTKR is the syndecan family of plasma membrane proteoglycans and, in particular, syndecan-4, which transmits FGF signalling via a protein kinase Calpha pathway. Another NTKR, alpha(v)beta(3) integrin, functions as an FGF signalling modulator by binding both FGF2 and FGFR1. Yet another NTKR, neural cell adhesion molecule (NCAM), can serve as an FGFR ligand and assemble an FGFR signalling complex in the absence of FGFs. Furthermore, N-cadherin, which has been reported to associate with FGFR, appears to activate FGFR in both ligand (FGF)-dependent and ligand-independent manners. Finally, gangliosides are implicated as a co-receptor system of FGFs. The biological consequence of non-canonical FGF signalling tends to be less discernable compared to the canonical FGFR activation because of the overlap between these two pathways; nevertheless, non-canonical signalling is important and sometimes essential for cellular functions. Given the diversity of FGF activities through embryonic development to adult physiology, the existence of the non-canonical signalling system may account for the different cellular response to the FGF input in different biological contexts. In this review, we will discuss recent findings related to non-canonical FGF signalling with emphasis on the endothelial biology and angiogenesis.
Cardiovasc Res 2008 May 01
PMID:Non-canonical fibroblast growth factor signalling in angiogenesis. 1805 63

We have recently demonstrated that tissue inhibitor of metalloproteinase-3 (TIMP-3) decreases neonatal cardiomyocyte proliferation (Hammoud L, Xiang F, Lu X, Brunner F, Leco K, Feng Q. Cardiovasc Res 75: 359-368, 2007). The aim of the present study was to delineate a pathway through which TIMP-3 exerts its antiproliferative effect. Experiments were conducted on neonatal cardiomyocyte cultures and heart tissues isolated from wild-type (WT) and TIMP-3(-/-) mice. Deficiency in TIMP-3 decreased p27 expression and increased cardiomyocyte proliferation in cardiomyocytes and neonatal hearts. A TIMP-3/epidermal growth factor (EGF) receptor (EGFR)/c-Jun NH(2)-terminal kinase (JNK)/SP-1/p27 pathway was investigated. JNK phosphorylation and EGFR protein levels were increased in TIMP-3(-/-) cardiomyocytes and heart tissues. Treatment with recombinant TIMP-3 decreased JNK phosphorylation and EGFR expression/phosphorylation. Inhibition of JNK activity using SP-600125 decreased SP-1 phosphorylation, increased p27 expression, and decreased cardiomyocyte proliferation. Furthermore, treatment with the EGFR specific inhibitor PD-168393 or the EGF-neutralizing antibody decreased cardiomyocyte proliferation as well as phosphorylation of JNK and SP-1 in both WT and TIMP-3(-/-) cardiomyocytes. We conclude that TIMP-3 inhibits neonatal mouse cardiomyocyte proliferation by upregulating p27 expression. The effects of TIMP-3 are mediated via inhibition of EGFR expression/phosphorylation, and decreases in JNK and SP-1 signaling.
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PMID:Tissue inhibitor of metalloproteinase-3 inhibits neonatal mouse cardiomyocyte proliferation via EGFR/JNK/SP-1 signaling. 1921 17

A 16-year-old male patient was admitted to the hospital for a medical workup to examine an anterior mediastinal tumor in April 2000. A tumor excision and a right lower lung lobe nodule resection were performed in June 2000. The tumor tissue showed a cobblestone-like proliferation of atypical cells containing a discrete nucleolus that were aligned in an epithelial fashion against mainly lymphocytic inflammatory cells in the background; also shown were undifferentiated tumor cells with epithelioid characteristics. Immunohistochemical staining for CD5, CD99, and KIT (CD117) revealed that the tumor cells were CD5-negative and that some of the lymphocytes infiltrating the tumor tissue stained positive for CD99 and negative for KIT. The lesion was therefore diagnosed to be a type B3 thymic epithelial tumor.
Ann Thorac Cardiovasc Surg 2009 Oct
PMID:Type B3 thymic epithelial tumor in an adolescent detected by immunohistochemical staining for CD5, CD99, and KIT (CD117): a case report. 1990 87

The use of the anticancer multikinase inhibitor sorafenib is associated with cardiac ischemia or infarction and an increase in hypertension. We investigated various mechanisms that might be responsible for its cardiotoxicity in a neonatal rat myocyte model. As measured by lactate dehydrogenase release, sorafenib treatment of myocytes caused dose-dependent damage at therapeutically relevant concentrations. It had been hypothesized that inhibition of RAF1 and BRAF kinases may be responsible for sorafenib induced cardiotoxicity. However, because sorafenib treatment did not inhibit phosphorylation of ERK (extracellular signal-regulated kinase), it was concluded that sorafenib did not exert its damaging effects through RAF inhibition of the RAF/MEK/ERK kinase cascade. The clinically approved doxorubicin cardioprotective agent dexrazoxane did not protect myocytes from damage. At lower sorafenib concentrations, at least, these results are consistent with sorafenib not being able to induce significant oxidative damage. In conclusion, given the extreme lack of kinase selectivity that sorafenib exhibits, it is likely that inhibition of kinases other than RAF, or combinations of kinases, contributes to the cardiotoxic effects of sorafenib.
Cardiovasc Toxicol 2010 Mar
PMID:Mechanisms of myocyte cytotoxicity induced by the multikinase inhibitor sorafenib. 1991 82

Inflammatory myofibroblastic tumour (IMT) or inflammatory pseudotumour is a histologically distinctive lesion occurring primarily in the viscera and soft tissue of children and young adults. We report an unusual case of IMT which had undergone malignant transformation in the chest wall at the pacemaker site. A 64-year-old male presented with a history of high fever, loss of appetite and weight loss of three months duration. He had a dual chamber pacemaker reinserted in the left infraclavicular region in the previous year. This was followed by a gradually enlarging hard swelling at the insertion site. The CT-scan showed a soft tissue mass encasing the pacing box, without intrathoracic extension. The trucut biopsy was suspicious of soft tissue sarcoma. A well encapsulated hard mass, with pacemaker embedded within it was resected en-bloc ensuring wide resection margins. Histology revealed fascicles of spindle cell proliferation with prominent inflammatory component, occasional spindle cells with prominent nucleoli and scattered atypical mitotic figures, with areas of focal necrosis. The lesional cells were negative for CD21, smooth muscle actin, ckit, cytokeratins and anaplastic lymphoma kinase 1. A diagnosis of IMT with malignant transformation i.e. inflammatory fibrosarcoma was made. He had adjuvant radiotherapy and uneventful recovery.
Interact Cardiovasc Thorac Surg 2010 Mar
PMID:Inflammatory myofibroblastic tumour at the pacemaker site. 2004 Apr 80

Pulmonary hypertension is a group of diseases comprising vascular constriction and obstructive changes of the pulmonary vasculature. Phosphodiesterase type 5 inhibitors, for example, sildenafil, can alleviate vascular remodeling in the monocrotaline pulmonary hypertension model in rats. We investigate the mechanisms of sildenafil on the pulmonary vascular remodeling of pulmonary hypertension induced by monocrotaline (MCT) in rats. Thirty Sprague-Dawley rats (weighing 200-220 g) were administered with MCT abdominal cavity injection or equivalent volume of normal saline (NS) (which were treated as C group n = 10) to induce pulmonary hypertension model. Fourteen days later, 20 MCT treated rats were randomly fed with sildenafil (25mg/kg/day) or placebo as S, P group (10 rats for each group), respectively. Another 6 weeks later, mean pulmonary artery pressure (mPAP), index of right ventricular hypertrophy (RV/LV+S) of all animals were measured under general anesthesia. Pulmonary tissue was collected to investigate pathological features of pulmonary arteries and to measure protein expression of ERK(1)/ERK(2) and MKP1. After 6 weeks, there were significant elevated mPAP and RV/LV+S in both P and S groups. The ratio of wall thickness to vessel diameter in pulmonary arteries with diameters <200 microm were increased in both P and S groups. But the ratio of wall thickness to vessel diameter was smaller in S group than that in P group. The phosphorylation level of ERK(1)/ERK(2) were elevated in both P and S groups, but the level of phosphorlation ERK(1)/ERK(2) were lower in S group than that in P group. Intriguingly, the expression level of MKP1 was significantly increased in both S and P groups, while it was higher in S group than that in P group. The sildenafil can decrease mPAP and inhibit the progress of pulmonary vascular remodeling in pulmonary hypertension rats. The ERK-MAP kinase signaling pathway might play a role during this process.
Cardiovasc Ther 2010
PMID:The extracellular signal-regulated kinase is involved in the effects of sildenafil on pulmonary vascular remodeling. 2007 56

The development of the so-called "targeted therapies", particularly those drugs that inhibit the activity of tyrosine kinases, has become a remarkable progress in the treatment of neoplastic diseases. The small molecule tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of chronic myeloid leukemia, and trastuzumab, the humanized monoclonal antibody against the ERBB2 receptor tyrosine kinase, has proved to have a high efficacy in 25% of breast cancers. On the basis of treatment success it is expected that targeted therapies will spread its use in the future. Recent data has shown that some of these therapies are associated with certain cardiotoxicity ranging from asymptomatic mild left ventricular dysfunction to congestive heart failure through different mechanisms. However, rates of cardiotoxicity associated with TKI are not well known mainly because clinical trials usually do not include predefined cardiac endpoints or the assessment of left ventricular function before and during treatment. In addition, it is especially difficult to diagnose heart failure in patients with some kinds of cancer who have many reasons to develop dyspnoea. Here we summarize what is known up to date about the cardiotoxicity of drugs targeting the tyrosine kinases. Being aware of the risk of using these drugs is particularly important to early detect and institute the appropriate treatment to prevent irreversible myocardial injury, especially when some neoplastic diseases, as haematological or breast cancers, can affect to young people with an estimated long-term survival.
Cardiovasc Hematol Agents Med Chem 2010 Jan
PMID:Cardiotoxicity of tyrosine-kinase-targeting drugs. 2021 Jul 73

The cardiotoxic potential of cytotoxic cancer chemotherapy is well known. Prime examples are the anthracyclines, which are highly efficacious agents for hemopoietic malignancies and solid tumors, but their clinical use is limited primarily by cardiotoxicity. Besides the conventional chemotherapeutics, new cancer drugs were developed in the last decade with the goal to specifically inhibit selected molecular targets such as growth factor receptors or intracellular tyrosine kinases in cancer cells. However, the outcome of combining conventional and newer cancer therapies could have unexpected side effects not anticipated so far and the long-term outcome is not known. Sometimes, however, unexpected side effects also shed light on previously unknown physiological functions. For example, the anti-HER2 cancer therapeutic trastuzumab (Herceptin), which can induce cardiac dysfunction, has demonstrated the importance of the ErbB/neuregulin signaling system in the adult heart. Subsequently, the role of endothelial-myocardial communication in maintaining phenotype and survival of adult cardiomyocytes has increasingly been recognized.
J Cardiovasc Pharmacol 2010 Aug
PMID:Cancer therapy-associated cardiotoxicity and signaling in the myocardium. 2038 57

Imipramine, an antidepressant drug, can cause potentially lethal cardiotoxic side effects including hypotension, ventricular tachycardia, and decreased cardiac output. This study investigated the mechanism responsible for imipramine-induced cardiac depression in rats. The left ventricular developed pressure (LVDP), velocity of the change in pressure (dP/dt), and heart rate (HR) accompanied with the total magnesium efflux ([Mg](e)) were measured in Langendorff-perfused intact rats hearts. Intracellular ionized magnesium concentrations ([Mg(2+)]( i)) were measured using Mag-fura 2 AM in a single H9c2 cell. The activation of the extracellular signal-regulated kinases 1/2 (ERK 1/2) was analyzed by Western blot. Imipramine induced reversible decreases in LVDP, dP/dt, and HR, which were accompanied by increases in [Mg](e). Imipramine also induced activation of ERK 1/2 and increase in the [Mg(2+)]( i), which was inhibited PD98059, ERK 1/2 inhibitor. These results suggest that imipramine-induced cardiac depression may be partly due to increases of [Mg(2+)](i) that are accompanied by the activation of ERK 1/2 in rats.
J Cardiovasc Pharmacol Ther 2010 Sep
PMID:Imipramine-induced cardiac depression is responsible for the increase in intracellular magnesium and the activation of ERK 1/2 in rats. 2048 20


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