Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since cold exposure confers cardioprotection, the present study attempted to determine the role of opioid receptors (OR). Stress with cold exposure and restraint for 3 h, shown previously to induce peptic ulcer in a synergistic manner, attenuated infarct size induced by myocardial ischemia and reperfusion in the isolated perfused rat heart from 36.64 +/- 1.8 to 22.85 +/- 2.6%. This is similar to protecting the rat with morphine at 8 mg/kg, which also attenuated the infarct size from 36.26 +/- 1.6 to 20.30 +/- 2.1%. The effects of cold-restraint or morphine were abolished by naloxone, a non-selective OR antagonist; nor-binaltorphimine, a selective kappa-OR antagonist; naltrindole, a selective delta-OR antagonist, or CTOP, a selective mu-OR antagonist. The effects were also attenuated by blockade of protein kinase C or the mitochondrial K(ATP) channel. The finding is first evidence that all three OR subtypes mediate cardioprotection of cold-restraint stress in the rat.
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PMID:Role of opioid receptors in cardioprotection of cold-restraint stress and morphine. 1559 68

Myocardial ischemia activates cardiac spinal afferents that transmit the nociceptive information leading to chest pain and elicit excitatory cardiovascular reflexes. Previous studies have shown that histamine is increased in coronary sinus blood during myocardial ischemia and that this autacoid stimulates abdominal visceral afferents. The present investigation evaluated the role of endogenous histamine in stimulation of ischemically sensitive cardiac spinal afferents. Nerve activity of single-unit cardiac afferents was recorded from the left sympathetic chain or rami communicans (T2-T5) in anesthetized cats. Sixty-four cardiac afferents were identified. Injection (5-30 microg/kg) of histamine into the left atrium (LA) stimulated 7 ischemically sensitive cardiac afferents resulting in a significant increase in their activity in a dose-dependent manner. Also, LA injection of histamine (10 microg/kg) stimulated 7 of 8 ischemically insensitive cardiac spinal afferents. Administrations of 2-(3-chlorophenyl)histamine (250 microg/kg, LA), a specific H1 receptor agonist and histamine (10 microg/kg, LA), stimulated 9 other ischemically sensitive cardiac afferents (0.48 +/- 0.10 to 1.40 +/- 0.20 imp/s). In contrast, dimaprit (500 microg/kg, LA), an H2 receptor agonist, stimulated only one of the 9 afferents and thus did not alter their overall activity (0.40 +/- 0.09 to 0.54 +/- 0.09 imp/s). (R)alpha-Methyl-histamine (500 microg/kg, LA), an H3 receptor agonist, did not stimulate any of the 9 afferents. Pyrilamine (300 microg/kg, i.v.), a selective H1 receptor antagonist, attenuated the activity of 8 afferents during 5 min of ischemia from 3.32 +/- 0.38 to 1.87 +/- 0.28 imp/s and abolished the response of 9 other cardiac afferents to histamine. Finally, administration of PKC-(19-36) (30 microg/kg, i.v.), a selective inhibitor of protein kinase C, attenuated the response of 8 cardiac afferents to histamine by 32%. These data indicate that endogenous histamine contributes to activation of cardiac sympathetic afferents during myocardial ischemia through H1 receptors and that the action of histamine on these cardiac afferents is partially dependent on the intracellular PKC pathway.
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PMID:Histamine contributes to ischemia-related activation of cardiac spinal afferents: role of H1 receptors and PKC. 1565 85

Connexin 43 (Cx43), a primary component of gap junctions, contributes to intercellular electrochemical communication. Cx43 undergoes dephosphorylation in early ischemia. We examined whether Cx43 is degraded in association with dephosphorylation during early myocardial ischemia and whether ischemic preconditioning (IP) affects the degradation after rat coronary artery occlusion. Male Sprague-Dawley rats underwent coronary artery occlusion for 1, 2, or 3 hours, or for 1 hour following treatment either with a calcineurin inhibitor (cyclosporine A), proteasome inhibitor (PSI), or lysosomal inhibitor (E64c), or following IP alone or after protein kinase C (PKC) inhibitor (chelerythrine) pretreatment. The IP was afforded by three cycles of 3 minute ischemia and 5 minute reperfusion. A large portion of the phosphorylated Cx43 (pCx43) in the membrane fraction was dephosphorylated, while a small portion was degraded at 1 hour of ischemia. The effects of the inhibitors were dephosphorylation and degradation by calcineurin and proteasome/lysosome, respectively. IP suppressed the decrease in pCx43 and increase in dCx43, while only the former was inhibited by the PKC inhibitor chelerythrine. The Cx43 mRNA level was reduced at 3 hours, but not at 1 hour of ischemia, irrespective of IP. We believe that Cx43 is dephosphorylated and degraded in early ischemia, whereas Cx43 transcription was suppressed at a later phase of ischemia.
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PMID:Down-regulation of connexin43 in early myocardial ischemia and protective effect by ischemic preconditioning in rat hearts in vivo. 1565 76

Protein kinase C (PKC) and angiotensin II (AngII) can regulate cardiac function in pathological conditions such as in diabetes or ischemic heart disease. We have reported that expression of connective tissue growth factor (CTGF) is increased in the myocardium of diabetic mice. Now we showed that the increase in CTGF expression in cardiac tissues of streptozotocin-induced diabetic rats was reversed by captopril and islet cell transplantation. Infusion of AngII in rats increased CTGF mRNA expression by 15-fold, which was completely inhibited by co-infusion with AT1 receptor antagonist, candesartan. Similarly, incubation of cultured cardiomyocytes with AngII increased CTGF mRNA expression by 2-fold, which was blocked by candesartan and a general PKC inhibitor, GF109203X. The role of PKC isoform-dependent action was further studied using adenoviral vector-mediated gene transfer of dominant negative (dn) PKC or wild type PKC isoforms. Expression of dnPKCalpha, -epsilon, and -zeta isoforms suppressed AngII-induced CTGF expression in cardiomyocytes. In contrast, expression of dominant negative PKCdelta significantly increased AngII-induced CTGF expression, whereas expression of wild type PKCdelta inhibited this induction. This inhibitory effect was further confirmed in the myocardium of transgenic mice with cardiomyocyte-specific overexpression of PKCdelta (deltaTg mice). Thus, AngII can regulate CTGF expression in cardiomyocytes through a PKC activation-mediated pathway in an isoform-selective manner both in physiological and diabetic states and may contribute to the development of cardiac fibrosis in diabetic cardiomyopathy.
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PMID:Differential regulation of angiotensin II-induced expression of connective tissue growth factor by protein kinase C isoforms in the myocardium. 1569 40

The aldose reductase pathway has been demonstrated to be a key component of myocardial ischemia reperfusion injury. Previously, we demonstrated that increased lactate/pyruvate ratio, a measure of cytosolic NADH/NAD+, is an important change that drives the metabolic cascade mediating ischemic injury. This study investigated signaling mechanisms by which the aldose reductase pathway mediates myocardial ischemic injury. Specifically, the influence of the aldose reductase pathway flux on JAK-STAT signaling was examined in perfused hearts. Induction of global ischemia in rats resulted in JAK2 activation followed by STAT5 activation. Pharmacological inhibition of aldose reductase or sorbitol dehydrogenase blocked JAK2 and STAT5 activation and was associated with lower lactate/pyruvate ratio and lower protein kinase C activity. Niacin, known to lower cytosolic NADH/NAD+ ratio independent of the aldose reductase pathway inhibition, also blocked JAK2 and STAT5 activation. Inhibition of protein kinase C also blocked JAK2 and STAT5 activation. Transgenic mice overexpressing human aldose reductase exhibited increased JAK2 and STAT5 activation. Pharmacological inhibition of JAK2 reduced ischemic injury and improved functional recovery similar to that observed in aldose reductase pathway inhibited mice hearts. These data, for the first time, demonstrate JAK-STAT signaling by the aldose reductase pathway in ischemic hearts and is, in part, due to changes in cytosolic redox state.
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PMID:Aldose reductase pathway mediates JAK-STAT signaling: a novel axis in myocardial ischemic injury. 1574 88

The cardioprotection of ischaemic preconditioning may be abolished in diabetic patients especially when some oral hypoglycaemics are used. The dose-response effect of gliclazide and glibenclamide on ischaemic preconditioning and the action of glibenclamide on signal transduction in human myocardium were investigated using right atrial appendages from cardiac surgery patients. Glibenclamide (0.1, 1, 3 and 10 microM) and gliclazide (1, 10, 30 and 100 microM) were added for 10 min prior to ischaemic preconditioning. The cardioprotection was abolished by glibenclamide at all concentrations and by gliclazide at supratherapeutic concentrations of 30 and 100 microM. Glibenclamide abolished the protective effect of mitoK(ATP) channel opening but not that of protein kinase C (PKC) or p38 mitogen activated protein kinase (p38MAPK) activation. In conclusion, glibenclamide and gliclazide differential effects may be a result of differential sensitivities. Glibenclamide does not block protection conferred by either PKC or p38MAPK activation. These findings may have clinical implications in ischaemic heart disease.
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PMID:The effect of gliclazide and glibenclamide on preconditioning of the human myocardium. 1589 5

Rapid nongenomic actions of aldosterone independent of mineralocorticoid receptors (MRs) on vascular tone are divergent. Until now, the rapid nongenomic actions of aldosterone on vascular tone of coronary artery and cardiac function in the in vivo ischemic hearts were not still fully estimated. Furthermore, although aldosterone can modulate protein kinase C (PKC) activity, there is no clear consensus whether PKC is involved in the nongenomic actions of aldosterone on the ischemic hearts. In open chest dogs, the selective infusion of aldosterone into the left anterior descending coronary artery (LAD) reduced coronary blood flow (CBF) in the nonischemic hearts in a dose-dependent manner. Also, in the ischemic state that CBF was decreased to 33% of the baseline, the intracoronary administration of aldosterone (0.1 nmol/L) rapidly decreased CBF (37.4+/-3.8 to 19.3+/-5.2 mL/100 g/min; P<0.05), along with decreases in fractional shortening (FS) (8.4+/-0.7 to 5.4+/-0.4%; P<0.05) and lactate extraction rate (LER) (-31.7+/-2.9 to -41.4+/-3.7%; P<0.05). The decrease in CBF was reproduced by the infusion of bovine serum albumin-conjugated aldosterone. Notably, these aldosterone-induced deteriorations of myocardial contractile and metabolic functions were blunted by the co-administration of GF109203X, an inhibitor of PKC, but not spironolactone. In addition, aldosterone activated vascular PKC. These results indicate that aldosterone nongenomically induces vasoconstriction via PKC-dependent pathways possibly through membrane receptors, which leads to the worsening of the cardiac contractile and metabolic functions in the ischemic hearts. Elevation of plasma or cardiac aldosterone levels may be deleterious to ischemic heart disease through its nongenomic effects.
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PMID:Aldosterone nongenomically worsens ischemia via protein kinase C-dependent pathways in hypoperfused canine hearts. 1595 16

Cardiac ischemia and reperfusion are associated with loss in the activity of the mitochondrial enzyme pyruvate dehydrogenase (PDH). Pharmacological stimulation of PDH activity improves recovery in contractile function during reperfusion. Signaling mechanisms that control inhibition and reactivation of PDH during reperfusion were therefore investigated. Using an isolated rat heart model, we observed ischemia-induced PDH inhibition with only partial recovery evident on reperfusion. Translocation of the redox-sensitive delta-isoform of protein kinase C (PKC) to the mitochondria occurred during reperfusion. Inhibition of this process resulted in full recovery of PDH activity. Infusion of the deltaPKC activator H2O2 during normoxic perfusion, to mimic one aspect of cardiac reperfusion, resulted in loss in PDH activity that was largely attributable to translocation of deltaPKC to the mitochondria. Evidence indicates that reperfusion-induced translocation of deltaPKC is associated with phosphorylation of the alphaE1 subunit of PDH. A potential mechanism is provided by in vitro data demonstrating that deltaPKC specifically interacts with and phosphorylates pyruvate dehydrogenase kinase (PDK)2. Importantly, this results in activation of PDK2, an enzyme capable of phosphorylating and inhibiting PDH. Thus, translocation of deltaPKC to the mitochondria during reperfusion likely results in activation of PDK2 and phosphorylation-dependent inhibition of PDH.
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PMID:Reperfusion-induced translocation of deltaPKC to cardiac mitochondria prevents pyruvate dehydrogenase reactivation. 1596 16

The link between endothelial nitric oxide synthase (eNOS) activation and vascular diameter during ischemia-reperfusion was investigated in the rat heart. After short (<30 min) and long (>45 min) time of ischemia conferred by coronary artery occlusion of the rats, reperfusion caused dilatation and constriction of arterioles, respectively. Partial oxygen pressure (pO2) measurement of the heart by the electrode confirmed the hyper-perfusion and no-reflow phenomena during reperfusion, as well as myocardial ischemia. The vascular diameter was correlated with phosphorylation of Akt and serine 1177 residue of eNOS, and formation of NO-bound guanylate cyclase (GC) by immuoflorescence study. Western blotting confirmed the phosphorylation of eNOS-Ser1177 depending on ischemia time. The constriction during reperfusion after 45 min of ischemia is supposedly caused by the inhibition of Akt-mediated eNOS-Ser1177 phosphorylation, which was suppressed by a PKC inhibitor chelerythrine, or ROS scavengers N-2-mercaptopropionyl glycine (MPG) and 4,5-Dihydroxy-1, 3-benzenedisulfonic acid disodium salt (Tiron). However, an endothelin receptor antagonist BQ123 alleviated the vasoconstriction by increasing NO availability but not eNOS-Ser1177 phosphorylation. Thus, vascular patency is correlated with eNOS-Ser1177 phosphorylation in association with ROS, and PKC during reperfusion. Endothelin inhibits vasodilatation by reducing NO availability during reperfusion.
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PMID:Endothelial NO Synthase (eNOS) phosphorylation regulates coronary diameter during ischemia-reperfusion in association with oxidative stress. 1603 23

We have investigated the effects of hypoxia and myocardial ischemia/reperfusion on the structure and function of cytochrome c oxidase (CcO). Hypoxia (0.1% O(2) for 10 h) and cAMP-mediated inhibition of CcO activity were accompanied by hyperphosphorylation of subunits I, IVi1, and Vb and markedly increased reactive O(2) species production by the enzyme complex in an in vitro system that uses reduced cytochrome c as an electron donor. Both subunit phosphorylation and enzyme activity were effectively reversed by 50 nm H89 or 50 nm myristoylated peptide inhibitor (MPI), specific inhibitors of protein kinase A, but not by inhibitors of protein kinase C. In rabbit hearts subjected to global and focal ischemia, CcO activity was inhibited in a time-dependent manner and was accompanied by hyperphosphorylation as in hypoxia. Additionally, CcO activity and subunit phosphorylation in the ischemic heart were nearly completely reversed by H89 or MPI added to the perfusion medium. Hyperphosphorylation of subunits I, IVi1, and Vb was accompanied by reduced subunit contents of the immunoprecipitated CcO complex. Most interestingly, both H89 and MPI added to the perfusion medium dramatically reduced the ischemia/reperfusion injury to the myocardial tissue. Our results pointed to an exciting possibility of using CcO activity modulators for controlling myocardial injury associated with ischemia and oxidative stress conditions.
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PMID:Protein kinase A-mediated phosphorylation modulates cytochrome c oxidase function and augments hypoxia and myocardial ischemia-related injury. 1630 65


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