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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We used phosphorus-31 nuclear magnetic resonance to test the ability of a perfluorocarbon blood substitute that has been shown in previous studies to improve oxygen delivery to hypothermic myocardium to maintain aerobic high-energy phosphate metabolism during total global ischemia. Twenty-three isolated perfused rabbit hearts were subjected to 180 min of hypothermic (23 degrees C) global ischemia followed by 45 min of normothermic reperfusion. Hearts received multiple doses of a cardioplegic solution that contained either oxygenated perfluorocarbon (Fluosol O2), nonoxygenated perfluorocarbon (Fluosol N2), or standard crystalloid hyperkalemic cardioplegic solution (STD-KCl) at 30 min intervals. Recovery of isovolumic left ventricular developed pressure (LVDP) was used to assess preservation of contractile function. Recovery of LVDP was 84 +/- 19% of preischemic control values with Fluosol O2, 68 +/- 16% with Fluosol N2, and 67 +/- 17% with STD-KCl (p = .058 vs Fluosol N2 and p = .056 vs STD-KCl). During 3 hr of ischemia intracellular pH (pHi) fell to 6.68 +/- 0.20 with STD-KCl and to 6.71 +/- 0.14 with Fluosol N2 but remained above 7.00 throughout the ischemic period with Fluosol O2 (p less than .0001 vs Fluosol N2 or STD-KCl). Myocardial ATP content was better preserved at 107 +/- 14% of control values with Fluosol O2 compared to 60 +/- 18% of control with Fluosol N2 and 75 +/- 21% of control with STD-KCl (p less than .001 vs Fluosol N2, p = .002 vs STD-KCl). Phosphocreatine (PCr) was also better preserved with Fluosol O2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Maintenance of aerobic metabolism during global ischemia with perfluorocarbon cardioplegia improves myocardial preservation. 669 19

Vascular endothelial growth factor (VEGF) is a secreted endothelial cell-specific angiogenic growth factor. VEGF gene transfer strategies to stimulate focal angiogenesis could be used to ameliorate myocardial ischemia. To induce angiogenesis in vivo, we have constructed a replication-defective herpes simplex virus type 1 (HSV-1) amplicon vector that places the human VEGF-165 cDNA under the transcriptional control of the HSV immediate-early 4/5 promoter (HSVhvegf). Transduction of NIH 3T3 fibroblasts with HSVhvegf resulted in the secretion of high levels of biologically active VEGF, as assayed by microvascular endothelial mitogenesis. By use of an ex vivo protocol, BLK-CL4 fibroblasts were transduced with HSVhvegf or control HSVlac virus (expressing Escherichia coli beta-galactosidase), resuspended in basement membrane extract (matrigel), and coinjected subcutaneously into syngeneic C57BL/6 mice. One week later, the matrigel plugs with HSVhvegf showed a strong angiogenic response, in contrast to the plugs with HSVlac-transduced fibroblasts. These data indicate that transduction with HSVhvegf virus can induce an angiogenic response in vivo and suggest that this is a viable gene therapy approach for tissue ischemia.
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PMID:Expression of vascular endothelial growth factor from a defective herpes simplex virus type 1 amplicon vector induces angiogenesis in mice. 753 Jun 6

The application of coronary angioplasty (PTCA) for early mechanical reperfusion in patients with evolving acute myocardial infarction (AMI) was introduced at the beginning of the '80s. There are 5 distinct approaches to PTCA for AMI mainly based on the timing of the intervention: primary or direct PTCA refers to emergency recanalization (as soon as possible) of the "culprit" vessel by the interventional procedure without the use of thrombolytic agents; immediate or sequential PTCA is the combination of administration of intravenous thrombolytic therapy followed very closely by PTCA; rescue PTCA refers to the use of PTCA as a mechanical approach for reperfusion when thrombolytic therapy has failed (60 to 120 min after such therapy has been initiated); deferred or adjunctive PTCA implies coronary angiography and PTCA delayed by at least several days after thrombolytic therapy and reserved for patients with residual ischemia; elective PTCA refers to a delayed symptom-derived procedure after thrombolytic therapy. Immediate PTCA, in which the procedure urgently follows the thrombolytic therapy has been studied in 3 randomized trials (TAMI 1, ECoS, TIMI 2A). All 3 trials have shown that immediate PTCA does not affect positively, but can worsen, the outcome of thrombolytic therapy since it increases mortality and bleeding complication with no improvement in reocclusion rate. Rescue PTCA was evaluated by several Authors who were able to demonstrate that mechanical reperfusion after failed thrombolytic therapy improves prognosis and reduces in-hospital and long-term mortality in this subgroup of patients with AMI. Deferred or adjunctive and elective PTCA represent therapeutic approaches in patients with residual ischemia following a successful thrombolysis able, when residual or recurrent ischemia are present, to prevent major cardiac events and to improve clinical outcome. The major interest was addressed to the role of primary PTCA in evolving AMI, as alternative therapy to thrombolysis. Randomized trials have been able to demonstrate that primary PTCA could dramatically improve the clinical outcome in AMI complicated by cardiogenic shock. Moreover, this approach can be safely performed in patients with contraindications for thrombolytic therapy with excellent results. Despite other advantages, primary or direct PTCA for evolving AMI is still presenting few points which have to be furtherly evaluated: acute or subacute reocclusion rates, restenosis rates, costs and availability to majority of population. The on-going clinical evaluation of other devices for mechanical reperfusion (transluminal extraction catheter-TEC, directional atherectomy, coronary stents, thermal PTCA, prolonged autoperfusion), in order to improve acute and subacute results, could furtherly expand the use of this approach in AMI-patients.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Role of direct coronary angioplasty in the course of acute myocardial infarction]. 802 10

A growing body of evidence has suggested that oxidative stress causes cardiac injuries during ischemia/reperfusion. Extracellular signal-regulated kinases (ERKs) have been reported to play pivotal roles in many aspects of cell functions and to be activated by oxidative stress in some types of cells. In this study, we examined oxidative stress-evoked signal transduction pathways leading to activation of ERKs in cultured cardiomyocytes of neonatal rats, and determined their role in oxidative stress-induced cardiomyocyte injuries. ERKs were transiently and concentration-dependently activated by hydrogen peroxide (H2O2) in cardiac myocytes. A specific tyrosine kinase inhibitor, genistein, suppressed H2O2-induced ERK activation, while inhibitors of protein kinase A and C or Ca2+ chelators had no effects on the activation. When CSK, a negative regulator of Src family tyrosine kinases, or dominant-negative mutant of Ras or of Raf-1 kinase was overexpressed, activation of transfected ERK2 by H2O2 was abolished. The treatment with H2O2 increased the number of cells stained positive by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and induced formation of DNA ladder and activation of CPP32, suggesting that H2O2 induced apoptosis of cardiac myocytes. When H2O2-induced activation of ERKs was selectively inhibited by PD98059, the number of cardiac myocytes which showed apoptotic death was increased. These results suggest that Src family tyrosine kinases, Ras and Raf-1 are critical for ERK activation by hydroxyl radicals and that activation of ERKs may play an important role in protecting cardiac myocytes from apoptotic death following oxidative stress.
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PMID:Oxidative stress activates extracellular signal-regulated kinases through Src and Ras in cultured cardiac myocytes of neonatal rats. 931 82

Rotationangioplasty and catheter atherectomy using the TEC device was performed in 33 patients with peripheral arterial occlusive disease. Thirty-five femoral or popliteal artery occlusions could be recanalized with an initial patency of 100%. After 5 years the patients were re-evaluated by clinical examination, colour duplex scanning and in 5 cases by intra-arterial angiography. According to life table analysis there was no patent femoral or popliteal vessel after 5 years in those patients treated initially for rest pain or ischemic tissue loss. 82% of those treated for claudication had a re-occluded artery. In 5 cases a major amputation was necessary. 42% of those patients who were initially treated far disabling claudication had a severe deterioration of their functional status with development of critical ischemia. In 9 of these cases reconstructive arterial surgery was required which failed in one patient with subsequent limb loss. In the retrospective study presented patients with occlusions up to 30 cm and more were treated. Combining two interventional techniques there is a high initial success rate with poor long term results. Therefore these devices should be reserved for high risk patients who would not tolerate reconstructive vascular surgery. They should not be used in patients with claudication although even extensive occlusions can be recanalized there is an imminent danger of causing significant deterioration of the patients functional status.
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PMID:Long term results after rotation angioplasty and catheter atherectomy. A retrospective analysis. 953 29

Vascular endothelial growth factor (VEGF) has been proposed to be among the candidate factors with the most potential to play a role in ischemia-induced collateral vessel formation. Recently, we found that VEGF activated the mitogen-activated protein kinase cascade in cultured rat cardiac myocytes. To elucidate how VEGF affects adhesive interaction of cardiac myocytes with the extracellular matrix (ECM), one of the important cell functions, we investigated the molecular mechanism of activation of focal adhesion-related proteins, especially focal adhesion kinase (p125(FAK)), in cultured rat cardiac myocytes. We found that the 2 VEGF receptors, KDR/Flk-1 and Flt-1, were expressed in cardiac myocytes and that KDR/Flk-1 was significantly tyrosine phosphorylated on VEGF stimulation. VEGF induced tyrosine phosphorylation and activation of p125(FAK) as well as tyrosine phosphorylation of paxillin; this was accompanied by subcellular translocation of p125(FAK) from perinuclear sites to the focal adhesions. This VEGF-induced activation of p125(FAK) was inhibited partially by the tyrosine kinase inhibitors genistein and tyrphostin. Activation of p125(FAK) was accompanied by its increased association with adapter proteins GRB2, Shc, and nonreceptor type tyrosine kinase p60(c-src). Furthermore, we confirmed that VEGF induced a significant increase in adhesive interaction between cardiac myocytes and ECM using an electric cell-substrate impedance sensor. These results strongly suggest that p125(FAK) is one of the most important components in VEGF-induced signaling in cardiac myocytes, playing a critical role in adhesive interaction between cardiac myocytes and ECM.
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PMID:Vascular endothelial growth factor induces activation and subcellular translocation of focal adhesion kinase (p125FAK) in cultured rat cardiac myocytes. 1034 94

The nonreceptor tyrosine kinase PYK2 represents a stress-sensitive mediator of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase (MAPK) signaling pathways in many cell types. In the present study, we assessed the tyrosine phosphorylation of PYK2 under normal and pathological conditions in the CNS. We generated a polyclonal antibody that selectively recognizes tyrosine-phosphorylated PYK2 at its major autophosphorylation site. By using this antibody, we demonstrate that the phosphorylation profile of PYK2 after focal cerebral ischemia is biphasic. The first phase occurs within 1 hr, when most of the phospho-PYK2 immunoreactivity was observed in cortical neurons, whereas 24-72 hr after ischemia, a striking induction of phospho-PYK2 immunoreactivity was evident in microglia around the necrotic infarcted area. Double-immunostaining analysis using both anti-phospho-PYK2 antibody and antibody against the double-phosphorylated active form of p38MAPK revealed that the two phosphorylated protein kinases exhibit strikingly similar distribution patterns after ischemia. A short time after ischemia, phosphorylation of p38MAPK was evident in the cortical neurons as demonstrated by both immunohistochemistry and immunoblotting analysis, whereas 24-72 hr after ischemia, phospho-p38MAPK was found in activated microglia and colocalized with phospho-PYK2. In contrast to cortical neurons, basal phospho-PYK2 immunoreactivity was observed in hippocampal pyramidal neurons, which was markedly decreased after kainate acid-induced status epilepticus. However, 24 hr after the epileptic onset, a pronounced upregulation of PYK2 and phospho-PYK2 immunoreactivities was evident in microglial cells, as demonstrated by double-immunostaining with the microglial marker OX42. These results provide, for the first time, in situ localization of tyrosine-phosphorylated PYK2 in neuronal stress pathways in the adult rat brain and are consistent with the role of PYK2 as an upstream regulator of p38MAPK signaling cascades in response to stress signals.
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PMID:Cerebral ischemia and seizures induce tyrosine phosphorylation of PYK2 in neurons and microglial cells. 1096 54

The protein kinase Akt/PKB has been implicated in antiapoptosis and neuronal survival. The authors now show that Akt is phosphorylated in the hippocampus during the early reperfusion period after 3.5 minutes bilateral carotid artery occlusion (BCAO) in the gerbil. Repeated sublethal ischemia induces ischemic tolerance, which is known as ischemic preconditioning. Ischemic preconditioning does not affect the amount of Akt protein, but rather decreases the phosphorylation of Akt at Ser-473 after 10 minutes reperfusion after 3.5 minutes BCAO. These results suggest that although Akt may play a role in neuronal survival after ischemia, it may not play a role in ischemic tolerance by preconditioning.
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PMID:Serine-threonine protein kinase Akt does not mediate ischemic tolerance after global ischemia in the gerbil. 1099 51

There have been many studies concerning the hemodynamics and physiological mechanisms in ischemic heart disease, little is known about molecular mechanisms during myocardial ischemia in in vivo study. As the signal transduction pathway responsible for myocardial hypertrophy and apoptosis, janus kinase (JAK) and signal transducers and activators of transcription (STAT) are suggested to play an important role. However, whether in vivo activation of JAK-STAT pathway occurs during myocardial ischemia is still unknown. The purpose of this study was to determine whether myocardial JAK or STAT is activated in ischemic heart, and to evaluate the angiotensin blockade on the pathway. Myocardial infarction was produced by ligation of the coronary artery in Wistar rats. After myocardial ischemia, we analysed both activated levels and total amounts of JAK1, JAK2, STAT1 and STAT3 by Western blot analyses at 0, 5, 15, 30, 60, 120 and 240 min. Compared with JAK activities at 0 min, JAK1 activities were significantly increased at 60 and 120 min (3.0- and 3.7-fold, respectively, P<0.01). JAK2 and STAT1 activities of ischemic myocardium were unchanged through the time course. STAT3 activities were increased at 5 min (3.3-fold, P<0.01) and markedly enhanced at 30, 60 and 120 min (4.6-, 7.7- and 8.7-fold, respectively, P<0.01). Pretreatment with imidapril (ACE inhibitor) and candesartan cilexitil (AT1 receptor antagonist) significantly prevented the increase in the phosphorylation of JAK1 at 120 min and STAT3 at 30 and 120 min. Sis-inducing factor (SIF) DNA complex was supershifted by specific anti-STAT3 antibody, indicating that increased SIF complex at least contained activated STAT3 proteins in ischemic myocardium. Imidapril and candesartan cilexitil inhibited the activation of SIF DNA binding at 1 day after coronary ligation. In conclusion, we showed that JAK1 and STAT3 were activated by ischemia from the basal activities in in vivo rat myocardial ischemia model. Imidapril and candesartan cilexitil prevented the increase in phosphorylated JAK1 and STAT3, thereby suggesting that angiotensin II, especially angiotensin II type I receptor, partially mediates activation of myocardial JAK-STAT pathway in acute myocardial ischemia.
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PMID:Myocardial ischemia activates the JAK-STAT pathway through angiotensin II signaling in in vivo myocardium of rats. 1116 35

Interaction between neutrophils and endothelial cells is one of the first steps in the functional response of polymorphonuclear neutrophils (PMN), and is necessary for their migration toward damaged tissues. PMN activation, leading to their adhesion to and migration between endothelial cells, is part of a complex phenomenon that can be altered in pathological situations such as the ischemia-reperfusion syndrome, in which large numbers of PMN are recruited to the tissue and release reactive oxygen species (ROS) near the vessel wall. ROS have been implicated in the pathogenesis of various inflammatory diseases. The increased adhesion of PMN to ROS-stimulated endothelial cells involves an increase in tyrosine phosphorylation of a tyrosine kinase focal adhesion kinase (p125FAK) and several cytoskeleton proteins, including paxillin and p130 cas. We examined the role of glutathione (GSH) in the regulation of this adhesion phenomenon and in the increased tyrosine phosphorylation induced by ROS. For this purpose we used anethole dithiolthione (ADT), which increases the glutathione synthesis by activating gamma-glutamyl-cysteine synthetase. We found that ADT reduced both PMN adhesion to ROS-stimulated human umbilical vein endothelial cells (HUVEC) and tyrosine phosphorylation of p125FAK and paxillin. ADT increased redox status by increasing intracellular GSH content in oxidized cells. These results show that GSH can reverse the effect of oxidation on tyrosine kinase activation and phosphorylation, and thus plays an important role in cell signaling. They also confirm the antioxidant activity of ADT.
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PMID:Anethole dithiolethione regulates oxidant-induced tyrosine kinase activation in endothelial cells. 1121 83


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