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)

Heat stress (HS) is known to protect against mechanical dysfunction and myocardial necrosis in myocardial ischemia-reperfusion models both in vivo and in vitro. However, the mechanisms involved in this form of cardioprotection remain unclear. Protein kinase C (PKC) and tyrosine kinase activation have both been shown to be involved in the delayed phase of protection following ischemic preconditioning, a phenomenon which appears to be analogous to HS-induced protection. Therefore, we investigated the role of PKC and tyrosine kinase in HS-induced resistance to myocardial infarction, in the isolated rat heart. The selective inhibitors chelerythrine (Che) and genistein (Gen) were used to inhibit PKC and tyrosine kinase, respectively. Rats were treated with Che (5 mg/kg, i.p.) or Gen (5 mg/kg, i.p.) or vehicle before they were either heat stressed (42 degrees C for 15 min) or sham anesthetized. Twenty-four h later their hearts were isolated, retrogradely perfused, and subjected to 35-min occlusion of the left coronary artery followed by 120-min of reperfusion. Infarct-to-risk ratio was significantly reduced in HS (19.9+/-1.1%) compared to sham (43.1+/-1.1%) hearts. This reduction in infarct size was abolished in chelerythrine-treated groups (43.8+/-1.9% in HS+Che v 44.9+/-2.0% in sham+Che), but was conserved in genistein-treated groups (17.7+/-0.9% in HS+Gen v 36.4+/-2.8% in sham+Gen). In order to confirm that genistein at this dose was effectively inhibiting tyrosine kinase activity, we observed the ability of the agent to prevent the hypoglycemic responses to insulin in a separate group of anesthetised rats receiving an i.v. insulin infusion. Western blot analysis of the myocardial hsp72 showed a HS-induced increase of this protein, which was modified by neither the PKC inhibitor, chelerythrine, nor the tyrosine kinase inhibitor, genistein. We conclude that the activation of PKC, but not of tyrosine kinase, appears to play a role in the functional cardioprotection associated with the heat stress response. Although protection appears to be dissociated from induction of hsp72, further work is required to explore the importance of hsp72 phosphorylation to cytoprotective activity of the protein.
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PMID:Protein kinase C is involved in resistance to myocardial infarction induced by heat stress. 944 37

Protein kinase C (PKC) has been suggested to mediate, at least in part, multiple processes in the pathophysiological sequelae of myocardial ischemia. The present study demonstrates that the epsilon, eta and iota isozymes of PKC are translocated to nuclei in response to brief intervals of global ischemia as well as reperfusion of ischemic rat myocardium. Concomitant with the translocation of PKC isozymes to nuclei during ischemia, increased PKC-mediated nuclear protein phosphorylation was observed. Taken together, the present results demonstrate that nuclear signaling mechanisms are activated during myocardial ischemia that include PKC translocation and PKC-mediated nuclear protein phosphorylation.
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PMID:Identification of specific nuclear protein kinase C isozymes and accelerated protein kinase C-dependent nuclear protein phosphorylation during myocardial ischemia. 982 54

Biological and mechanical stressors such as ischemia, hypoxia, cellular ATP depletion, Ca2+ overload, free radicals, pressure and volume overload, catecholamines, cytokines, and renin-angiotensin may independently cause reversible and/or irreversible cardiac dysfunction. As a defense against these forms of stress, several endogenous self-protective mechanisms are exerted to avoid cellular injury. Adenosine, a degradative substance of ATP, may act as an endogenous cardioprotective substance in pathophysiological conditions of the heart, such as myocardial ischemia and chronic heart failure. For example, when brief periods of myocardial ischemia precede sustained ischemia, infarct size is markedly limited, a phenomenon known as ischemic preconditioning. We found that ischemic preconditioning activates the enzyme responsible for adenosine release, ie, ecto-5'-nucleotidase. Furthermore, the inhibitor of ecto-5'-nucleotidase reduced the infarct size-limiting effect of ischemic preconditioning, which establishes the cause-effect relationship between activation of ecto-5'-nucleotidase and the infarct size-limiting effect. We also found that protein kinase C is responsible for the activation of ecto-5'-nucleotidase. Protein kinase C phosphorylated the serine and threonine residues of ecto-5'-nucleotidase. Therefore, we suggest that adenosine produced via ecto-5'-nucleotidase gives cardioprotection against ischemia and reperfusion injury. Also, we found that plasma adenosine levels are increased in patients with chronic heart failure. Ecto-5'-nucleotidase activity increased in the blood and the myocardium in patients with chronic heart failure, which may explain the increases in adenosine levels in the plasma and the myocardium. In addition, we found that further elevation of plasma adenosine levels due to either dipyridamole or dilazep reduces the severity of chronic heart failure. Thus, we suggest that endogenous adenosine is also beneficial in chronic heart failure. We propose potential mechanisms for cardioprotection attributable to adenosine in pathophysiological states in heart diseases. The establishment of adenosine therapy may be useful for the treatment of either ischemic heart diseases or chronic heart failure.
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PMID:Adenosine and cardioprotection in the diseased heart. 1047 69

Protein kinase C (PKC), p38 MAP kinase, and mitogen-activated protein kinase-activated kinases 2 and 3 (MAPKAPK2 and MAPKAPK3) have been implicated in ischemic preconditioning (PC) of the heart to reduce damage following a myocardial infarct. This study examined whether extracellular signal-regulated kinase (Erk) 1, p70 ribosomal S6 kinase (p70 S6K), casein kinase 2 (CK2), and other hsp27 kinases are also activated by PC, and if they are required for protection in rabbit hearts. CK2 and hsp27 kinase activities declined during global ischemia in control hearts, whereas PC with 5 min ischemia and 10 min reperfusion increased their activities during global ischemia. Resource Q chromatography resolved two distinct peaks of hsp27 phosphotransferase activities; the first peak (at 0.36 M NaCl) appeared to correspond to the 55-kDa MAPKAPK2. Erk1 activity was elevated in both control and PC hearts after post-ischemic reperfusion, but no change was observed in p70 S6K activity. Infarct size (measured by triphenyltetrazolium staining) in isolated rabbit hearts subjected to 30 min regional ischemia and 2 h reperfusion was 31.0+/-2.6% of the risk zone in controls and was 10.3+/-2.2% in PC hearts (p<0.001). Neither the CK2 inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) nor the Mek1/2 inhibitor PD98059 infused during ischemia blocked protection by PC. The activation of CK2 and Erk1 in ischemic preconditioned hearts appear to be epiphenomena and not required for the reduction of infarction from myocardial ischemia.
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PMID:Ischemia induced activation of heat shock protein 27 kinases and casein kinase 2 in the preconditioned rabbit heart. 1066 33

The characterization of biological processes on the basis of alterations in the cellular proteins, or "proteomic" analysis, is a powerful approach that may be adopted to decipher the signaling mechanisms that underlie various pathophysiological conditions, such as ischemic heart disease. This review represents a prospectus for the implementation of proteomic analyses to delineate the myocardial intracellular signaling events that evoke cardioprotection against ischemic injury. In concert with this, the manifestation of a protective phenotype has recently been shown to involve dynamic modulation of protein kinase C-epsilon (PKC epsilon) signaling complexes (Ping P, Zhang J, Pierce WM Jr, and Bolli R. Circ Res 88: 59--62, 2001). Accordingly, "the signaling module hypothesis" is formulated as a plausible mechanism by which multipurpose stress-activated proteins and signaling kinases may function collectively to facilitate the genesis of cardioprotection.
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PMID:Use of functional proteomics to investigate PKC epsilon-mediated cardioprotection: the signaling module hypothesis. 1124 51

In this program of studies we have characterized in detail the translocation (assessed by Triton-insolubility) and phosphorylation (using serine-45 or -59 phosphospecific antibodies) of alphaB crystallin during myocardial ischemia [both with or without ischemic preconditioning (IPC)]. Pharmacological activators and inhibitors allowed us to characterize the signaling pathways involved in alphaB crystallin phosphorylation during ischemia. Ischemic preconditioning alone caused 30% of the heart's alphaB crystallin pool to translocate, providing a significant translocation 'head-start' in protected tissue. This enhanced translocation is coupled with increased (3-fold) alphaB crystallin phosphorylation at both serine residues. The possible role of alphaB crystallin in the protection afforded by ischemic preconditioning is supported by the signal transduction data; which showed preconditioning-induced alphaB crystallin phosphorylation can be blocked by tyrosine kinase inhibition (using genistein) and by p38 MAP kinase or PKC inhibition (using SB203580 or bisindolylmaleimide, respectively). The activation of both p38 MAP kinase and PKC are recognized requirements for the induction of preconditioning and their inhibition is known to block protection. Western immunoblotting analysis after isoelectric focusing electrophoresis, confirmed the observations made with the phosphospecific antibodies; but also showed that 27+/-4% of total cardiac crystallin was phosphorylated after 30 min of ischemia. AlphaB crystallin exists as large polymeric aggregates in cardiac tissue under basal conditions (approximately 1 MDa as determined by gel filtration chromatography). We induced phosphorylation of alphaB crystallin during aerobic perfusion by the administration of phenylephrine. However this treatment did not alter the molecular aggregate size of alphaB crystallin. It appears that alphaB crystallin molecular aggregate size is not simply regulated by phosphorylation. AlphaB crystallin may have a role to play in the myocardial protection induced by ischemic preconditioning, as both translocation and phosphorylation are both accelerated and enhanced by ischemic preconditioning.
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PMID:AlphaB crystallin translocation and phosphorylation: signal transduction pathways and preconditioning in the isolated rat heart. 1154 45

Apolipoprotein AI (apo AI) is the major protein component of serum high-density lipoproteins. The abundance of apo AI correlates inversely with the risk of ischemic heart disease (IHD) and thus enhanced expression of the protein is expected to reduce the risk of IHD. Our previous studies show that insulin enhances apo AI promoter activity and this action requires the GC-rich insulin response core element (IRCE, -411 to -404). The motif binds to a ubiquitous transcription factor Sp1. We have extended studies that examine insulin induction of apo AI using a 41 bp (-425 to -385) fragment of apo AI DNA linked to the trout metallothionein TATA box and fused to luciferase (pIRCE-Luc). Luc activity in Hep G2 cells transfected with pIRCE-Luc was stimulated by insulin, an insulin mimetic bisperoxo (1,10-phenanthroline) oxovanadate (bpv) and the phorbol ester (PDBu). Our previous studies showed that insulin action on apo AI gene transcription flowed down two signaling pathways: Ras-raf and PI3K, leading to activation of the MAPK and PKC kinases, respectively. In contrast, PDBu activates only the PKC pathway. Although insulin and PDBu activation of apo AI were distinct, the cascades involved all appeared to target Sp1. Furthermore, exposure of transfected cells to okadaic acid or a phosphatase inhibitor also increased Luc activity and suggested a potential role for phosphorylation, likely involving Sp1. If true, then changes in the IRCE binding activity of Sp1 should be detected following exposure to MAPK, PKC, or the protein phosphatase I (PPI) alone and in various combinations followed by assaying the ability of Sp1 to bind the IRCE. Sp1 binding activity increased with either MAPK or PKC. Although exposure to PPI also affected IRCE binding activity of Sp1, whether it increased or decreased was dependent on the order of exposure to the protein. In summary, the IRCE alone can mediate the stimulatory effects of insulin, bpv, and PDBu, and Sp1 enhances these responses that may arise from phosphorylation of the protein.
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PMID:Insulin induction of apolipoprotein AI, role of Sp1. 1261 63

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

In certain cardiovascular disorders, such as congestive heart failure and ischemic heart disease, several endogenous regulators, including norepinephrine (NE) and endothelin-1 (ET-1), are released from various types of cell. Because plasma levels of these regulators are elevated, it seems likely that cardiac contraction might be regulated by crosstalk among these endogenous regulators. We studied the regulation of cardiac contractile function by crosstalk between ET-1 and NE and its relationship to Ca2+ signaling in canine ventricular myocardium. ET-1 alone did not affect the contractile function. However, in the presence of NE at subthreshold concentrations (0.1 to 1 nmol/L), ET-1 had a positive inotropic effect (PIE). In the presence of NE at higher concentrations (100 to 1000 nmol/L), ET-1 had a negative inotropic effect. ET-1 had a biphasic inotropic effect in the presence of NE at an intermediate concentration (10 nmol/L). The PIE of ET-1 was associated with an increase in myofilament sensitivity to Ca2+ ions and a small increase in Ca2+ transients, which required the simultaneous activation of protein kinase A (PKA) and PKC. ET-1 elicited translocation of PKCepsilon from cytosolic to membranous fraction, which was inhibited by the PKC inhibitor GF 109203X. Whereas the Na+-H+ exchange inhibitor Hoe 642 suppressed partially the PIE of ET-1, detectable alteration of pHi did not occur during application of ET-1 and NE. The negative inotropic effect of ET-1 was associated with a pronounced decrease in Ca2+ transients, which was mediated by pertussis toxin-sensitive G proteins, activation of protein kinase G, and phosphatases. When the inhibitory pathway was suppressed, ET-1 had a PIE even in the absence of NE. Our results indicate that the myocardial contractility is regulated either positively or negatively by crosstalk between ET-1 and NE through different signaling pathways whose activation depends on the concentration of NE in the dog.
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PMID:Signal transduction and Ca2+ signaling in contractile regulation induced by crosstalk between endothelin-1 and norepinephrine in dog ventricular myocardium. 1269 35

There is increasing evidence that cyclooxygenase (COX)-2 possess both angiogenic and cardioprotective properties. We examined the effects of hypoxic cardiac myocytes (H9c2 cells) on COX-2 expression in human umbilical vein endothelial cells (HUVECs) to determine the pathway involved in COX-2 regulation. The medium from hypoxic (<1% O2) cardiac myocytes (HMCM) or normoxic cardiac myocytes (21% O2) was added to HUVEC cultures. HMCM induced a transient increase of COX-2 mRNA expression at 1 and 3 h without affecting the COX-1 mRNA level. A similar effect also observed in HMCM from cultured primary cardiac myocytes (rat neonatal cardiac myocytes). The increased COX-2 mRNA was associated with a time-dependent increase in COX-2 protein expression. COX-2 was significantly induced by VEGF (4.86 +/- 1.03-fold) and IL-1beta (3.93 +/- 0.89-fold) and slightly increased by TNF-alpha but not by FGF2, IGF-1, or PDGFs. Analysis of proteins secreted in HMCM showed increased levels of VEGF but not IL-1 beta or TNF-alpha. The HMCM-induced COX-2 expression was inhibited by the addition of an anti-VEGF neutralizing antibody. VEGF induced endothelial cell COX-2 expression by both increasing COX-2 transcription and prolonging the COX-2 mRNA half-life. Furthermore, staurosporine, a nonselective PKC inhibitor, prevented the induction of VEGF by hypoxia. Both a selective PKC-alpha and -beta inhibitor and an inducible nitric oxide synthase (NOS) inhibitor decreased the induction of COX-2 by HMCM and VEGF. Finally, HMCM-induced upregulation of COX-2 was accompanied by upregulation of PGI2 and PGE2. These results suggest that VEGF is one of the principal factors produced by hypoxic myocytes that is responsible for the induction of endothelial cell COX-2 expression. This process likely involves both PKC and NOS pathways. Our findings have important implications regarding the cardiac protection of COX-2 in ischemic heart disease.
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PMID:Hypoxia induces myocyte-dependent COX-2 regulation in endothelial cells: role of VEGF. 1288 Dec 20


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