Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Met-enkephalin (Met-enk) has been demonstrated to modulate myocardial-ischemia mechanisms via the opioid receptors, but no studies are now available on Met-enk levels in the coronary circulation. In this experience Met-enk levels were evaluated in aortic root and in coronary sinus at baseline (T0), during PTCA induced transient ischemia (T1) and during reperfusion (T2). No significant differences were found at any time. Thus, it appears that there is no Met-enk extraction from the coronary circulation during provoked myocardial ischemia and no Met-enk release from the ischemic heart.
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PMID:Met-enkephalin levels during PTCA-induced myocardial ischemia. 1144 49

Recent investigations conducted with human neutrophils have indicated an involvement for the receptor for formylated peptides, termed FPR, and its analog FPRL1 (or ALXR because it is the receptor for the endogenous ligand lipoxin A(4)) in the in vitro inhibitory actions of the glucocorticoid-regulated protein annexin 1 and its peptidomimetics. To translate these findings in in vivo settings, we have used an ischemia/reperfusion (I/R) procedure to promote leukocyte-endothelium interactions in the mouse mesenteric microcirculation. In naive mice, the annexin 1 mimetic peptide Ac2-26 (20 to 100 microg administered intravenously prior to reperfusion) abolished I/R-induced cell adhesion and emigration, but not cell rolling. In FPR-deficient mice, peptide Ac2-26 retained significant inhibitory actions (about 50% of the effects in naive mice), and these were blocked by an FPR antagonist, termed butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe, or Boc2. In vitro, neutrophils taken from these animals could be activated at high concentrations of formyl-Met-Leu-Phe (30 microM; fMLP), and this effect was blocked by cell incubation with peptide Ac2-26 (66 microM) or Boc2 (100 microM). FPR-deficient neutrophils expressed ALXR mRNA and protein. Both ALXR agonists, lipoxin A(4) and peptide Ac2-26, provoked detachment of adherent leukocytes in naive as well as in FPR-deficient mice, whereas the CXC chemokine KC or fMLP were inactive. The present findings demonstrate that endogenous regulatory autocoids such as lipoxin A(4) and annexin 1-derived peptides function to disengage adherent cells during cell-cell interactions.
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PMID:Leukocyte antiadhesive actions of annexin 1: ALXR- and FPR-related anti-inflammatory mechanisms. 1256 Feb 18

Recently, we reported that exogenous administration of Met(5)-enkephalin (ME) for 24 h reduces infarct size after ischemia-reperfusion in rabbits. In the present study, we tested whether ME-induced cardioprotection is exhibited in murine hearts and whether chronic infusion of this peptide can render hearts tolerant to ischemia. Barbiturate-anesthetized open-chest mice (C57BL/6J) were subjected to regional myocardial ischemia-reperfusion (45 min of occlusion and 20 min of reperfusion). Mice received saline vehicle or ME for 24 h or 2 wk before undergoing regional myocardial ischemia-reperfusion or for 24 h followed by a 24-h delay before regional myocardial ischemia-reperfusion. Infarct size was measured with propidium iodide and is expressed as a percentage of the area at risk. Infarcts were smaller after infusion of ME for 24 h than with vehicle control: 49.2 +/- 9.0% vs. 22.2 +/- 3.2% (P < 0.01). In contrast, administration of ME for 2 wk failed to elicit cardioprotection: 36.5 +/- 9.1% and 41.4 +/- 8.2% for control and ME, respectively (P = not significant). When a 24-h delay was imposed between the end of drug treatment and the onset of the ischemic insult, cardioprotection was lost: 38.5 +/- 6.1% and 42.8 +/- 6.6% for control and ME, respectively (P = not significant). Chronic sustained exogenous infusion of the endogenously produced opioid peptide ME is associated with loss of the cardioprotection that is observed with 24 h of infusion. Furthermore, in this in vivo murine model, ME failed to induce delayed tolerance to myocardial ischemia-reperfusion.
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PMID:Long-term infusion of Met5-enkephalin fails to protect murine hearts against ischemia-reperfusion injury. 1555 May 29

Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic hemolytic anemia and thrombocytopenia, accompanied by microvascular thrombosis that causes variable degrees of tissue ischemia and infarction. Intravascular coagulation is not a prominent feature of the disorder. Plasma exchange can induce remissions in approximately 80% of patients with idiopathic TTP, but patients have a much worse prognosis when thrombotic microangiopathy is associated with cancer, certain drugs, infections, or tissue transplantation. Recently, acquired autoimmune deficiency of a plasma metalloprotease named ADAMTS13 was shown to cause many cases of idiopathic TTP. This review describes our current understanding of how to use this knowledge clinically. In Section I, Dr. Joel Moake describes the presentation of thrombotic microangiopathy, emphasizing the pathophysiology of idiopathic TTP. Platelets adhere to ultra-large (or "unusually large") von Willebrand factor (ULVWF) multimers that are immobilized in exposed subendothelial connective tissue and secreted into the circulation in long "strings" from stimulated endothelial cells. ADAMTS13 cleaves ULVWF multimers within growing platelet aggregates under flowing conditions, and this normally limits platelet thrombus formation. If ADAMTS13 is absent, either congenitally or due to acquired autoantibodies, platelet-rich microvascular thrombosis proceeds unchecked and TTP ensues. Plasma exchange is effective therapy for idiopathic TTP, probably because it replenishes the deficient ADAMTS13 and removes some of the pathogenic autoantibodies and endothelial-stimulating cytokines. Some patients have a type of thrombotic microangiopathy after transplantation/chemotherapy but do not have severe ADAMTS13 deficiency. The pathogenesis of their disease must differ but remains poorly understood. In Section II, Dr. Toshiyuki Miyata describes recent advances in assay methods that should facilitate routine laboratory testing of ADAMTS13 for patients with thrombotic microangiopathy. ADAMTS13 cleaves a single Tyr-Met bond in domain A2 of the VWF subunit. ADAMTS13 assays based on the cleavage of plasma VWF multimers have been used extensively but require considerable time and expertise to perform. A recombinant substrate containing 73 amino acid residues of VWF domain A2 has been devised that allows short incubation times and rapid product detection by gel electrophoresis or immunoassay. These results should encourage the development of even simpler assays that can be performed in most clinical laboratories. In Section III, Dr. James George provides an update on the long-term prospective study of thrombotic microangiopathy in the Oklahoma TTP-HUS Registry. At presentation, the clinical distinction between idiopathic TTP, various forms of secondary thrombotic microangiopathy, and even Shiga toxin-associated hemolytic uremic syndrome (HUS) can be problematic because the symptoms and laboratory findings often overlap. Consequently, plasma exchange usually is administered to any patient with thrombotic microangiopathy if there is doubt about the cause. The role of ADAMTS13 testing in choosing therapy remains uncertain, but the results do appear to have prognostic significance. Severe ADAMTS13 deficiency is specific for idiopathic TTP and identifies a subgroup with a high likelihood of response to plasma exchange, and high-titer ADAMTS13 inhibitors correlate strongly with a high risk of relapsing disease. Patients with normal ADAMTS13 activity have a much worse prognosis, although many factors probably contribute to this difference. Longitudinal study of these patients will continue to clarify the relationship of ADAMTS13 deficiency to the clinical course of thrombotic microangiopathy.
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PMID:Recent advances in thrombotic thrombocytopenic purpura. 1556 95

Our previous studies indicated that opioid-induced cardioprotection occurs via activation of mitochondrial ATP-sensitive K(+) (K(ATP)) channels. However, other elements of the Met(5)-enkephalin (ME) cardioprotection pathway are not fully characterized. In the present study, we investigated the role of tyrosine kinase, MAPK, and phosphatidylinositol 3-kinase (PI3K) signaling in ME-induced protection. Ca(2+)-tolerant, adult rabbit cardiomyocytes were isolated by collagenase digestion and subjected to simulated ischemia for 180 min. ME was administered 15 min before the 180 min of simulated ischemia; blockers were administered 15 min before ME. Cell death was assessed by trypan blue as a function of time. The epidermal growth factor receptor (EGFR) kinase inhibitor AG-1478 (250 nM) blocked ME-induced protection, but the inactive analog AG-9 (100 microM) did not. Treatment with herbimycin (1 microM) completely eliminated ME-induced protection. To verify that ME activates EGFR and to determine the involvement of Src, Western blotting of EGFR was performed after ME administration with and without herbimycin A. ME resulted in herbimycin-sensitive robust phosphorylation of EGFR at Tyr(992) and Tyr(1068). Administration of the selective MAPK inhibitor PD-98059 (10 nM) and the specific MEK1/2 inhibitor U-0126 (10 microM) also inhibited ME-induced cardioprotection. ME-induced ERK1/2 phosphorylation was significantly reduced by PD-98059, the EGFR kinase inhibitor PD-153035 (10 microM), and chelerythrine (2 microM). The PI3K inhibitor LY-294002 (20 microM) abrogated ME-induced protection, and ME-induced Akt phosphorylation at Ser(473) was suppressed by LY-294002, PD-153035, and chelerythrine. We conclude that ME-induced cardioprotection is mediated via Src-dependent EGFR transactivation and activation of the PI3K and MAPK pathways.
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PMID:Met5-enkephalin-induced cardioprotection occurs via transactivation of EGFR and activation of PI3K. 1556 40

Adaptive responses associated with environmental stressors are critical to cell survival. Under conditions when cellular redox and antioxidant defenses are overwhelmed, the selective oxidation of critical methionines within selected protein sensors functions to down-regulate energy metabolism and the further generation of reactive oxygen species (ROS). Mechanistically, these functional changes within protein sensors take advantage of the helix-breaking character of methionine sulfoxide. The sensitivity of several calcium regulatory proteins to oxidative modification provides cellular sensors that link oxidative stress to cellular response and recovery. Calmodulin (CaM) is one such critical calcium regulatory protein, which is functionally sensitive to methionine oxidation. Helix destabilization resulting from the oxidation of either Met(144) or Met(145) results in the nonproductive association between CaM and target proteins. The ability of oxidized CaM to stabilize its target proteins in an inhibited state with an affinity similar to that of native (unoxidized) CaM permits this central regulatory protein to function as a cellular rheostat that down-regulates energy metabolism in response to oxidative stress. Likewise, oxidation of a methionine within a critical switch region of the regulatory protein phospholamban is expected to destabilize the phosphorylation-dependent helix formation necessary for the release of enzyme inhibition, resulting in a down-regulation of the Ca-ATPase in response to beta-adrenergic signaling in the heart. We suggest that under acute conditions, such as inflammation or ischemia, these types of mechanisms ensure minimal nonspecific cellular damage, allowing for rapid restoration of cellular function through repair of oxidized methionines by methionine sulfoxide reductases and degradation pathways after restoration of normal cellular redox conditions.
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PMID:Redox modulation of cellular signaling and metabolism through reversible oxidation of methionine sensors in calcium regulatory proteins. 1568 Feb 20

Attraction of mononuclear cells to sites of inflammation requires a close interplay of the inflammatory signal presented via chemokines and specific receptors on effector cells. First studies on acute renal transplant rejection demonstrated the involvement of CC-chemokines, such as RANTES, MIP-1alpha, MIP-1beta and MCP-1, as well as CXC-chemokines such as IL-8 and IP-10, correlating with expression of the corresponding chemokine receptors, CCR1, CCR5 and CCR2 as well as CXCR3. Since then, the pathophysiologic relevance has been extended to chronic allograft nephropathy and transplant glomerulopathy. Chemokine expression can be triggered by different stimuli, e.g. brain death, ischemia, HLA-mismatch and infection. Furthermore, anti-inflammatory chemokines have been identified. Chemokine receptor 7, e.g. enhances homing of lymphocytes to lymphatic tissues and the Duffy antigen receptor, DARC, a non-specific receptor that binds and inactivates different chemokines. While measurement of chemokine expression in clinical transplantation may facilitate the differential diagnosis of allograft dysfunction, knowledge of the chemokine network has also widened the understanding of transplant rejection and opened novel therapeutic approaches. Observations from humans with mutations of the chemokine network as well as transplantation of animals with targeted deletions in this system suggest that manipulations of chemokine signalling may improve the success rates of transplantation. Blocking chemokines unselectively with Met-RANTES or specifically with small molecule inhibitors of various chemokine receptors has lead to improved outcome in animal models. Currently, first human trials are under way to investigate drugs that stimulate lymphocyte homing. Inhibitors of CCR1 and CCR5 are being tested for other human diseases and may eventually be available in transplantation. Nonetheless, chemokine blockade my rather serve as an adjunct in the management of transplant recipients than a new "magic bullet".
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PMID:Chemokines and chemokine receptors in renal transplantation--from bench to bedside. 1744 76

Using The globally ischaemic isolated guinea-pig heart we conducted studies to assess the role of activated neutrophils (PMNs) and the role of the endothelium in reperfusion injury. Reperfusion injury was induced by a 20 min period of global ischaemia followed by a 30 min reperfusion with Krebs' buffer supplemented with f-Met-Leu-Phe (fMLP) and heparinized blood. Ischaemia alone or blood alone resulted in a complete recovery in contractile function measured by developed pressure, fMLP (500 muM) and blood, administered to normoxic hearts did not affect contractile function. The combination of 100 muM fMLP and blood beginning at reperfusion and continuing for 30 min decreased the recovery in contractile function (max. 33 +/- 6% reovery) while buffer and 100 pM fMLP resulted in a complete recovery in function. In hearts infused with buffer and neutropenic blood incubated with 100 muM fMLP a complete recovery in function was observed. Isolated peritoneal neutrophils, 7-70 x 10(5) PMN/ min, incubated with 100 muM fMLP and Krebs' solution decreased contractile function in a concentration-related manner (max. 44 +/- 11% recovery). Platelets, plasma or red blood cells alone incubated with fMLP did not decrease recovery in developed pressure. Platelets and PMN incubated with 100 muM fMLP did not, while red blood cells and PMN did, elicit a reduction in recovery in contractile function (34 +/- 4% recovery). A 20 min period of global ischaemia destroys the functional integrity of the endothelium (response to Ach). Pre-treatment of the heart with sufficient H(2)O(2) to functionally damage the endothelium, followed by infusion of Krebs' solution supplemented with blood and 100 muM fMLP also elicited a reduction in recovery of contractile function (42 +/- 15% recovery). In summary, partially activated neutrophils play a major role in reperfusion injury and there exists a cooperativity between the RBC and PMN in this model.
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PMID:The role of the neutrophil and formed elements of the blood in an in vitro model of reperfusion injury. 1847 8

The efficacy of copper aspirinate against thrombotic diseases has been tested in animal models. The results show that copper aspirinate, following ig pretreatment for 7 days at 0.012mmol/kg markedly prolonged the bleeding time and inhibited the mortality induced by arachidonic acid (AA) in mice. On cereral ischemia model pretreatment with 0.018mmol/kg copper aspirinate ig significantly increased survival of animals and the density of intact hippocampal CA1 cells and decreased brain calcium concentration. Its anticerebral ischemia activity was superior to or equal to nimodipine. It is, therefore, suggested that copper aspirinate is very promising in becoming an antithrombotic drug in preventing and treating thrombotic diseases.
Met Based Drugs 1998
PMID:Potential application of copper aspirinate in preventing and treating thromboembolic diseases. 1847 33

The cerebroprotective effects of copper aspirinate [dimeric copper(II) bis(o-acetoxybenzoate)] were investigated in gerbils subjected to 10-min global cerebral ischemia followed b 60-min reperfusion. The results showed that intragastric copper aspirinate (7.5, 15.0 and 30.0 mg Kg(-1)) markedly promoted the recovery of the electroencephalogram amplitude, attenuated the increase of lipid peroxide content and the decrease of superoxide dismutase activity in the cortex during ischemia-reperfusion injury. It suggested that copper aspirinate possesses potential neuroprotective properties, the mechanism of which might be related to an increase of the activity of endogenous superoxide dismutase.
Met Based Drugs 2002
PMID:Cerebroprotective Effects of Dimeric Copper(II) Bis(o-acetoxybenzoate) on Ischemia-reperfusion Injury in Gerbils. 1847 2


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