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)

Continuous coronary perfusion with warm beta-blocker-enriched blood has been suggested as an alternative to cardioplegic arrest for myocardial protection during coronary artery surgery. The purpose of the present work was 1.) to experimentally investigate this technique using an animal model, and 2.) to clinically apply this alternative myocardial protection technique and compare it to standard crystalloid cardioplegia in a controlled study. We placed 6 dogs on CPB and 6 dogs on a biventricular assist device and created "beta-blocker-induced cardiac surgical conditions" by suppressing myocardial chronotropy and inotropy with systemic infusion of the ultra-short acting beta-blocker esmolol. For the clinical study we randomized 60 coronary artery surgery patients to receive either crystalloid cardioplegia (Bretschneider HTK) or selective continuous coronary perfusion via the aortic root with warm esmolol-enriched CPB blood. In the experimental study we found that continuous coronary perfusion with warm esmolol-enriched blood avoided myocardial ischemia and minimized myocardial edema, thus completely preserving cardiac performance. Our clinical data showed the alternative technique to be superior to standard crystalloid cardioplegia in terms of both functional and structural myocardial protection. The concept of beta-blocker-induced cardiac surgical conditions is a useful alternative for myocardial protection during coronary artery surgery and may be particularly beneficial for severely compromised hearts.
Thorac Cardiovasc Surg 1997 Oct
PMID:Improved myocardial protection using continuous coronary perfusion with normothermic blood and beta-blockade with esmolol. 961 18

In human heart transplantation limited myocardial ischemia duration remains one of the most restricting factors. A new approach towards prolongation of this duration is the combination of cardioplegic arrest and continuous Coronary Oxygen Persufflation (COP) with gaseous oxygen. This technique, which is based on former experiments, was applied in pig hearts which we transplanted orthotopically after a hypothermic preservation time of 14 hours. For cardioplegic arrest we used either Euro-Flush glutathion solution (EFG; n=5), University of Wisconsin solution (UW; n=5), modified Bretschneider HTK cardioplegic solution (mHTK; n=6). In preliminary experiments all three solutions had shown equal cardioprotective qualities. Hearts of the mHTK group were submitted to continuous COP during storage (mHTK+COP). After 14 hours of preservation and orthotopic transplantation the mHTK+COP hearts showed significantly improved cardiac functional recovery compared to hearts preserved by simple cold storage techniques. Hemodynamics measured after 3 hours reperfusion were significantly better in the mHTK+COP group compared to EFG and UW: dp/dtmax in % of baseline+/-standard deviation (SD): 85+/-22, 65+/-26, 36+/-15, CO in % of baseline: 68+/-13, 35+/-8, 39+/-8. Postoperative preload recruitable stroke work in the mHTK+COP hearts was: 51.4+/-23.1 mmHg compared to preoperative: 57.3+/-17.2. ATP of left-ventricular myocardium in the mHTK+COP group: 14.7+2.1 micromol/g dry weight was significantly higher compared to EFG: 10.3+/-4.5 and UW: 5.9+/-3.2. CK-MB in percent of CK in all groups showed no increase during postoperative reperfusion. This study suggests that COP may present an effective complement to cold storage techniques currently used in heart transplantation. Prior to clinical application further investigations regarding long-term survival and endothelial function are required.
Thorac Cardiovasc Surg 1998 Sep
PMID:Coronary oxygen persufflation for long-term myocardial protection. 982 85

The extent and distribution of myocardial edema induced by perfusion with cardioprotective solutions is of great interest. Domestic pig hearts (n = 12) were perfused in situ after aortic cross clamping either with Bretschneider's cardioplegic solution (HTK, 4 degrees C, n = 3), with a heparinized Krebs-Henseleit solution containing 30 mmol/L 2,3 Butanedionemonoxime (BDM, 4 degrees C, n = 3) or with heparinized pig blood (HPB, 24 degrees C, n = 3). After a three-hours storage period, magnetic resonance tomography (MRI) was carried out. The acquired T1-weighted data were used for the subsequent three-dimensional reconstruction based on the "Heidelberg ray-tracing technique". The small myocardial tissue blocks (n = 216) were excised from these hearts for dry weight measurements for 9 preselected regions in duplicate including ventricular papillary muscle, ventricular free wall, ventricular septum, apex, and atrial tissue. In control hearts (n = 3), dry weight was measured immediately after explantation (no MRI). The results of dry-weight measurements and three dimensional visualization were compared. Dry-weight measurements revealed that considerable myocardial edema is induced by any of the experimental procedures. The effects were most pronounced after BDM perfusion. Regardless how the edema was induced, there were significant differences of the water content within the heart: the water content in the heads of the papillary muscles and in the interventricular septum was always smaller than that of the free left- and right-ventricular walls. The heterogeneity of myocardial edema and its spatial distribution pattern could be qualitatively visualized. The experimental data (biophysical data and 3D visualization) clearly show a heterogeneity of myocardial edema induced by different types of cardioprotective solutions. As the presence of myocardial edema represents one of the crucial events in the pathophysiology of myocardial dysfunction occurring during myocardial infarction, ischemia, heart transplantation, and extracorporeal circulation, the present study represents an interesting contribution towards intravital detection and distribution of myocardial edema.
Thorac Cardiovasc Surg 1998 Oct
PMID:Heterogeneity of myocardial edema in isolated pig hearts after perfusion with different types of cardioprotective solutions. 988 20

Troglitazone (TRO) is an oral insulin-sensitizer that has direct effects on the vasculature to inhibit cell growth and migration. In vascular smooth muscle cells (VSMCs), insulin transduces a mitogenic signal that is dependent on the ERK1/2 MAP kinases. We examined the effects of TRO on this pathway and found that it inhibits mitogenic signaling. In quiescent VSMCs, insulin (1 microM) induced a 3.2-fold increase in DNA synthesis. TRO (1-20 microM) inhibited insulin-stimulated DNA synthesis by 72.8% at the maximal concentration. TRO at I and 10 microM had no significant effect on insulin-stimulated ERK1/2 activity. At 20 microM, however, TRO modestly enhanced insulin-stimulated ERK1/2 activity by 1.5-fold. ERKs transduce a mitogenic signal by phosphorylating transcription factors such as Elk-1. which regulate critical growth-response genes. We used GAL-Elk-1 expression plasmids to detect ERK-dependent activation of Elk-1. TRO at 1-20 microM potently inhibited insulin-stimulated, ERK1/2-dependent Elk-1 transcription factor activity. Neither early steps in insulin signaling nor the phosphatidylinositol 3-kinase (PI3K) branch of this pathway were affected by TRO, because it had no effect on IRS-1 phosphorylation, PI3K/IRS-1 association, or Akt phosphorylation. Because TRO is a known ligand for the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), we tested two other ligands for this receptor, rosiglitazone (RSG) and 15-deoxy-delta12,14 prostaglandin J2 (15d-PGJ2). Both also inhibited insulin-induced DNA synthesis. In summary, these data show that TRO inhibits mitogenic signaling by insulin at a point distal of ERK1/2 activation, potentially by a PPARgamma-mediated inhibition of ERK-dependent phosphorylation and activation of nuclear transcription factors that regulate cell growth.
J Cardiovasc Pharmacol 2000 May
PMID:Troglitazone inhibits mitogenic signaling by insulin in vascular smooth muscle cells. 1081 77

Our previous studies suggested a protective role of the extracellular signal-regulated kinases (ERKs) cascade in ischemic preconditioning (IP) in the porcine heart. To test this hypothesis further, we studied the influence of the novel specific inhibitors of mitogen-activated protein kinase kinases (MEK 1/2) PD98059 (PD) and UO126 (UO) in IP. The substances were infused intramyocardially and UO also systemically in anesthetized, ventilated, open-chested, male pigs. The local intramyocardial PD and UO infusions occurred before IP and during both reperfusion (RP) phases of IP via four pairs of needles (three pairs verum, one solvent) into the risk area (RA). The IP design included two cycles of 10-min left anterior descending artery (LAD) occlusion and 10 min RP, followed by 40 min of occlusion (index ischemia) and of 60 min of RP. Biopsies of the areas of drug infusion were taken after the second RP cycle of IP. By Western blot analysis, the phosphorylation of ERK 1/2 and of the downstream transcription factor Elk-1 were measured, and the activities of the ERKs were tested by in gel phosphorylation. Only small infarcts were detected in the control group animals with the IP period [infarct size (IS), infarct area/risk area; IS, 2.5+/-0.1%]. Significant wedge-shaped infarcts were seen around the area of the PD and UO infusions. The effects of PD and UO were concentration dependent. The maximal dose of UO126 (7.5 mg systemically) was associated with an IS of 68.7+/-2.0%. At the end of IP, we observed a significant increase in phosphorylation and activities of ERKs. PD (50 microM) induced a 50% inhibition of ERK-1 and 56% of ERK-2 activities. Phosphorylated ERK-1 and ERK-2 were decreased after microinfusion of both PD and UO (50 microM). Microinfusion of 50 microM PD also significantly decreased the phosphorylation of Elk-1 (to 59.2+/-8.3% of control conditions). We demonstrate for the first time in vivo that the inhibition of ERKs by PD and UO results in a complete cancellation of IP.
J Cardiovasc Pharmacol 2000 Aug
PMID:Inhibition of the ER-kinase cascade by PD98059 and UO126 counteracts ischemic preconditioning in pig myocardium. 1094 64

The central role of vascular endothelial growth factor (VEGF) in angiogenesis in health and disease makes it attractive both as a therapeutic target for anti-angiogenic drugs and as a pro-angiogenic cytokine for the treatment of ischaemic heart disease. While VEGF binds to two receptor protein tyrosine kinases, VEGFR1 (Flt-1) and VEGFR2 (KDR), most biological functions of VEGF are mediated via VEGFR2, and the role of VEGFR1 is currently unknown. Neuropilin-1, a non-tyrosine kinase transmembrane molecule, may function as a co-receptor for VEGFR2. Considerable progress has recently been made towards delineating the signal transduction pathways distal to activation of VEGFR2. Activation of the mitogen-activated protein kinase, protein kinase C and Akt pathways are all strongly implicated in mediating diverse cellular biological functions of VEGF, including cell survival, proliferation, the generation of nitric oxide and prostacyclin and angiogenesis. Upregulation of metalloproteinases, activation of focal adhesion kinase and interactions between VEGF receptors and integrins are strongly implicated in VEGF-induced endothelial cell migration. Recent findings suggest important roles for the vasodilators nitric oxide and prostacyclin, in linking post-receptor signaling networks to downstream biological effects and in mediating some in vivo endothelial functions of VEGF.
Cardiovasc Res 2001 Feb 16
PMID:Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. 1116 70

ErbB4 is a member of the epidermal growth factor receptor (EGFR, ErbB) family that mediates responses to neuregulins and other EGF-like growth factors. ErbB4 is a central regulator of cardiovascular and neural development as well as differentiation of the mammary gland. A role for ErbB4 has also been implicated in malignancies and heart diseases. Four structurally and functionally distinct ErbB4 isoforms have recently been identified. One pair of isoforms differs within their extracellular juxtamembrane domains. These juxtamembrane ErbB4 isoforms are either susceptible or resistant to proteolytic processing that release a soluble receptor ectodomain. Another pair of ErbB4 isoforms differs within their cytoplasmic tails. Analysis of the intracellular signal transduction pathways indicates that both cytoplasmic ErbB4 isoforms can couple to the Shc-MAPK signaling pathway, while the other one is incapable of coupling to the phosphoinositide 3-kinase (PI3-K)-Akt pathway. The differences in the activation of signaling cascades are reflected in the cellular responses stimulated via the cytoplasmic isoforms. Both cytoplasmic ErbB4 isoforms can stimulate proliferation, but the isoform that cannot activate PI3-K is defective in stimulating cellular survival and chemotaxis. Together these four naturally occurring receptor variants provide a new level of diversity to the control of growth factor-stimulated cellular responses. Thus, the ErbB4 isoforms may have distinct and specific roles in the regulation of various developmental and pathological processes.
Trends Cardiovasc Med 2000 Oct
PMID:Erbb4 and its isoforms: selective regulation of growth factor responses by naturally occurring receptor variants. 1134 71

Phosphatidylinositol 3-kinase (PI-3K) controls important intracellular steps involved in inflammation, immunity, and cell growth. PI-3K also modulates leukocyte integrin adhesiveness. In this study we evaluated the role of PI-3K on neutrophil adhesion to intercellular adhesion molecule-1 (ICAM-1)-transfected cells. N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated neutrophil adhesion was inhibited by wortmannin and LY294002, two unrelated PI-3K inhibitors, whereas phorbol myristate acetate (PMA)-induced neutrophil adhesion was not inhibited by them. After fMLP stimulation, a rapid activation of AKT and ERK was observed. However, only activation of AKT was reversed by the PI-3K inhibitors. Neutrophil expression of the beta2-integrins Mac-1, lymphocyte function-associated antigen-1(LFA-1), and gp150.95 was not affected by wortmannin, nor was expression of the activation epitope recognized by MAB24. We conclude that (a) PI-3K is involved in fMLP-activated neutrophil adhesion to ICAM-1-transfected cells, (b) the mechanism involved is not mediated by the modulation of beta2-integrin expression or activation, and (c) another mechanism seems to involve the adhesion to ICAM-1 when a cellular system of adhesion is used.
J Cardiovasc Pharmacol 2001 Jun
PMID:Evidence for the involvement of phosphatidylinositol 3-kinase in fMLP-stimulated neutrophil adhesion to ICAM-1-transfected cells. 1139 72

The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) exert numerous cellular effects through the inhibition of cholesterol synthesis. The objectives of these experiments were to determine the following: (1) whether lovastatin (LOV) inhibits phenylephrine (PE)-induced growth of neonatal rat cardiac myocytes without inducing cytotoxicity and (2) whether growth-inhibiting effects of LOV are associated with reduced PE activation of extracellular signal regulated kinases 1 and 2 (ERK 1/2). After 48 h of exposure, LOV alone (0.1-10 microM) inhibited 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide (MTT) reduction without significant changes in propidium iodide staining, and 100 microM mevalonic acid prevented the effect of LOV on MTT reduction. PE (50 or 100-microM for 48 h) induced significant increases in protein-to-DNA ratios. PE (100 microM for 5 min) significantly increased the phosphorylated forms of ERK 1 and ERK 2 and activity of ERK. After 24 h pretreatment or 48 h cotreatment, LOV (10 microM) significantly inhibited PE-induced growth. In addition, LOV pretreatment significantly inhibited the stimulatory effect of PE on ERK 2 phosphorylation and ERK activity. These results demonstrate that LOV, at concentrations that do not alter membrane integrity, inhibits PE-induced growth of cardiac myocytes, potentially through reduced activation of ERK 1/2.
Cardiovasc Toxicol 2001
PMID:Lovastatin inhibits phenylephrine-induced ERK activation and growth of cardiac. 1221 76

An inflammatory pseudotumor (IPT), known as a plasma cell granuloma, is a relatively uncommon neoplasm with an unidentified etiology. To our knowledge, an early relapse with multiple lung nodules following lung resection and occurrences in multiple organs is extremely rare. The patient was a 49-year-old man who presented with left chest pain and fever. A chest film demonstrated an 8x8 cm mass in the left lower lobe. During thoracotomy in April 2001, a mass was seen to have invaded the diaphragm with remarkable pleural adhesion. The intraoperative pathological diagnosis was infiltration of inflammatory cells with no malignancy. Therefore, a partial resection of the left lower lobe was performed. Three months after the thoracotomy, a chest CT scan disclosed multiple nodular opacities bilaterally, and an open lung-biopsy of the right lung was performed in January 2002. His past history included an excision of a mass on the penis in another hospital in 1994 and a subcutaneous mass that appeared on the right thigh and disappeared spontaneously following a needle biopsy in 1999. Pathologically there was no fundamental difference among his present lesion and the former two. The pathological diagnosis at each occurrence was inflammatory pseudotumor (IPT). In immunohistochemical study, the staining with smooth muscle actin cells was positive, but was negative for the staining with anaplastic lymphoma kinase (ALK). With no evidence of a neoplastic process, these histopathological and immunohistochemical findings could imply that this case may be a postinflammatory reparative reaction, although his condition exhibited the clinically aggressive behavior of suspected lung metastasis.
Ann Thorac Cardiovasc Surg 2002 Aug
PMID:A case report of inflammatory pseudotumor of the lung: rapid recurrence appearing as multiple lung nodules. 1247 87


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