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)

Columbus, Ohio added prehospital coronary care to its Emergency Medical Services System (EMS) in 1969. The EMS System, which is citizen activated and tax supported (+5 per citizen per year), currently sees 32,000 patients a year in a city with a population of 650,000. Ninety-six per cent of the population is aware of the system. Over two thirds of patients with ischemic sudden death or myocardial infarction are seen by advanced life support paramedic (EMT-P) units. The EMT-Ps operate by protocol without telemetry and carry all standard resuscitative drugs and devices. Serial evaluations have shown that within the limits of the protocol, the EMT-Ps perform as effectively as physicians in diagnosis and care of acute cardiovascular emergencies, including endotracheal intubation. One third of ischemic cardiac arrest patients in whom resuscitation is possible (60% of such patients seen) are discharged from the hospital alive (14.2/100,000 lives saved per year). Lives are also saved by treatment of other life-threatening prehospital complications. In Columbus, the estimated annual mortality from ischemic heart disease is only 19%. The EMS System contributes significantly to this low figure.
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PMID:The role of paramedics in resuscitation of patients with prehospital cardiac arrest from coronary artery disease. 651 10

14C-misonidazole was injected IP into BALB/C mice bearing EMT-6 tumours. Tumour and normal tissue levels of radioactivity were determined by liquid scintillation procedures for times up to 72 h after drug administration. At times longer than 8 h, levels of 14C in tumour were 2-6 times higher than 14C levels measured in other normal tissues, with the exception of liver. The levels of 14C from misonidazole retained in liver tissue were comparable to those retained in the tumours. The clearance of 14C-misonidazole from the tumours and all normal tissues could be characterised by two distinct phases: a rapid phase (0.7 h half-life) followed by a much slower phase (approximately 50 h half-life). The distribution of retained 14C from labelled misonidazole within tumour-bearing mice was also measured by whole animal autoradiographic techniques. This procedure confirmed the biodistribution of 14C-misonidazole determined by liquid scintillation procedures. To enhance binding to hypoxic cells in vivo, 14C-misonidazole was administered in multiple doses over a three-hour period, simulating a prolonged exposure to the drug. The 14C from labelled misonidazole retained in tumour tissue was 4-15 times greater than that retained in normal tissues, liver tissue being again an exception. Myocardial ischaemia was induced by isoproterenol treatment and a two-fold increase of 14C from labelled misonidazole was found in the heart tissue of mice treated by the drug compared to controls. The increased binding of 14C-misonidazole to tumour cells after prolonged exposure to the drug and the increased binding of 14C-misonidazole to ischaemic heart tissue suggests that hypoxia is a factor in sensitiser adduct formation in vivo.
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PMID:The labelling of EMT-6 tumours in BALB/C mice with 14C-misonidazole. 661 39

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

Forty patients (34 males and 6 females) with neurological complaints/manifestations and with a past history of multiple sexual partners attending the Government Rajaji Hospital, Madurai, India between April 1992 and October 1992 were investigated for neurosyphilis. Metabolic disorders, hypertension, ischaemic heart disease, arrhythmias and trauma were excluded. Seven males (17.5%) were found to have neurosyphilis. The youngest was 26 years old and the oldest was 47. All were married and of low socioeconomic background. Meningovascular syphilis was the predominant presentation (6:1). Associated cardiovascular involvement was noticed in one of the cases. There was no associated HIV infection in these cases. The incidence is higher than previous reports from this centre.
Int J STD AIDS
PMID:Prevalence of neurosyphilis at Government Rajaji Hospital, Madurai, India. 794 62

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

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.
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PMID:Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. 1116 70

We recently demonstrated that ischemic preconditioning (IPC) induced by cyclic episodes of short durations of ischemia and reperfusion potentiates a signal transduction cascade involving protein tyrosine kinases and MAP kinases. A rapid activation of janus kinase (JAK) and several signal transducers and activators of the transcription (STATs) including STAT3, STAT5A and STAT6 has been shown to occur during myocardial ischemia and reperfusion. This study sought to examine if JAK/STAT signaling pathway play any role in classical early phase of IPC. Isolated working rat hearts were perfused for 15 min with KHB buffer in the absence or presence of a JAK kinase inhibitor tyrphostin AG490 (5 microm) followed by IPC, 30 min global ischemia and 2 h of reperfusion. The results demonstrated extensive phosphorylation of JAK2 and STAT3 in the IPC hearts which was almost completely abolished by an inhibitor of JAK2, AG490. IPC displayed cardioprotection as evidenced by improved post-ischemic contractile recovery, decreased myocardial infarct size and reduced number of apoptotic cardiomyocytes. AG490 blocked IPC-mediated cardioprotection by altering the IPC-mediated survival signal into death signal. Thus, IPC-induced upregulation of antiapoptotic gene bcl-2 and downregulation of pro-apoptotic gene bax are decreased and increased, respectively, in the AG490 treated hearts. The results suggest that early phase of IPC potentiates JAK/STAT signaling by activating STAT3 which transmits a survival signal to the myocardium.
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PMID:Role of STAT3 in ischemic preconditioning. 1170 38

The Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway is a stress-responsive mechanism that transduces signals from the cell surface to the nucleus, thereby modulating gene expression. Recent studies have demonstrated that myocardial ischemia and reperfusion induce rapid activation of this pathway. Although the functional consequences of this event remain to be elucidated, there is emerging evidence that JAK-STAT signaling plays an important role in the development of the cardioprotected phenotype associated with ischemic preconditioning. Specifically, brief episodes of myocardial ischemia/reperfusion activate JAK1 and JAK2, followed by recruitment of STAT1 and STAT3, resulting in transcriptional upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), which then mediate the infarct-sparing effects of the late phase of preconditioning. The present review focuses on this novel cardioprotective role of JAK-STAT signaling and on its potential exploitation for developing therapeutic strategies aimed at limiting ischemia/reperfusion injury.
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PMID:Role of the JAK-STAT pathway in protection against myocardial ischemia/reperfusion injury. 1258 43

Apoptosis of cardiac myocytes is thought to be a feature of many pathological disorders, including congestive heart failure (CHF) and ischemic heart disease (IHD). Because recent investigations indicate that endothelin-1 (ET-1) plays an important role in CHF and IHD, we investigated the effect of ET-1 on cardiomyocyte apoptosis. The presence of apoptosis in rat cardiomyocytes (H9c2 and neonatal) was evaluated by morphological criteria, electrophoresis of DNA fragments, 4',6'-diamidine-2'-phenylindole staining, and TUNEL analysis. ET-1, but not angiotensin II, prevented apoptosis induced by serum deprivation via ETA receptors in a dose-dependent manner (1 to 100 nmol/L). ET-1 also prevented cytochrome c release from mitochondria to the cytosol. The use of specific pharmacological inhibitors demonstrated that the antiapoptotic effect of ET-1 was mediated through a tyrosine kinase pathway (genistein and AG490) but not through protein kinase C (PKC; calphostin C), mitogen-activated protein kinases (PD98059 and SB203580), or PKA (KT5270) pathways. Adenovirus-mediated gene transfer of kinase-inactive (KI) c-Src reversed the antiapoptotic effect of ET-1. We further investigated whether Bcl-xL, an antiapoptotic molecule, would be upregulated by using a luciferase-based reporter system. ET-1 upregulated Bcl-xL, and this upregulation was inhibited by genistein or AG490 but not by calphostin C. The experiments with KI mutants for various tyrosine kinases revealed that c-Src and Pyk2 (but not JAK1, Jak2, Syk, and Tec) are involved in ET-1-induced upregulation of Bcl-xL expression. These findings suggest that ET-1 prevents apoptosis in cardiac myocytes through the ETA receptor and the subsequent c-Src/Bcl-xL-dependent pathway.
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PMID:Antiapoptotic effect of endothelin-1 in rat cardiomyocytes in vitro. 1266 84

We recently demonstrated that ischemic preconditioning (PC) induced by cyclic episodes of short duration of ischemia and reperfusion potentiates a signal transduction cascade involving Janus kinase (JAK) 2 and signal transducer and activator of transcription 3 (STAT3). A rapid activation of JAK and several STATs, including STAT3, STAT5A, and STAT6 also occurred during myocardial ischemia and reperfusion. This study sought to examine whether STAT5A and STAT6 were also involved in PC. Two different animal models were used: isolated perfused working rat hearts and STAT5A and STAT6 knockout mouse hearts. The results of our study indicated phosphorylation of STAT 5A and STAT6 in the preconditioned myocardium. Tyrphostin AG490, a JAK2 inhibitor, or 4-amino-5-(4-methylphenyl)-7-(t-butyl)-pyrazolo-3,4-d-pyrimidine (PPI), a Src kinase blocker, blocked STAT5A phosphorylation, whereas STAT6 phosphorylation was blocked only with tyrphostin. As expected, significant cardioprotection was achieved in the preconditioned heart as evidenced by reduced myocardial infarct size and decreased number of apoptotic cardiomyocytes. PC-mediated cardioprotection was partially abolished when hearts were pretreated with tyrphostin, PPI, or LY-294002, a phosphatidylinositol (PI)-3 kinase inhibitor. Studies with STAT5A and STAT6 knockout mouse hearts revealed that STAT6 knockout mouse hearts, and not STAT5A knockout mouse hearts, were resistant to myocardial ischemia-reperfusion injury. The hearts from STAT5A knockout mice could not be preconditioned, whereas those from STAT6 knockout mice were easily preconditioned. The results of the present study demonstrate that STAT5A, and not STAT6, plays a role in ischemic PC. For the first time, the results also indicated a role of Src kinase pathway in STAT5A PC and PI-3 kinase-Akt pathways appear to be the downstream regulator for STAT5A-STAT6 signaling pathway.
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PMID:STAT signaling in ischemic heart: a role of STAT5A in ischemic preconditioning. 1286 May 60


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