Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In acute myocardial infarction the occurrence of malignant arrhythmias and the spreading of the infarcted zone followed by the development of heart failure determine the clinical outcome of the disease. The activity of the adrenergic system plays an important role in both. At various levels acute myocardial ischaemia induces an inadequate activation of the adrenergic system. The increased presynaptic release of endogenous catecholamines does not promote the expected desensitization at the postsynaptic level. In contrast, acute ischaemia leads to a rapid and persistent increase of functionally coupled beta-adrenergic receptors, which in the early phase of acute ischaemia, induce an increased responsiveness of the adenylyl cyclase system to beta-adrenergic stimulation. This sensitization at the receptor level is superimposed by a receptor-independent sensitization of the adenylyl cyclase and a loss of tonic inhibition due to the functional impairment of the inhibitory G protein. At the enzyme level a transient sensitization of adenylyl cyclase in acute myocardial ischaemia is due to a modification of the enzyme, which is tightly associated with the purified enzyme. Only inhibition of protein kinase C is able to block completely the ischaemia-induced sensitization of adenylyl cyclase. Based on these data, it could be demonstrated that acute myocardial ischaemia leads to a rapid activation of protein kinase C by an as yet undefined mechanism. Beyond the sensitization of adenylyl cyclase, activation of protein kinase C may directly activate ion channels or the N+/H+ echanger, and it may induce the increased expression of oncogenes and thus crucially influence the clinical outcome of an acute myocardial infarction.
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PMID:Sensitization of the beta-adrenergic system in acute myocardial ischaemia by a protein kinase C-dependent mechanism. 166 55

Increased sympathetic activity has been documented in patients during acute myocardial infarction. Clinical and experimental studies have suggested that this increased sympatho-adrenergic activation may contribute to the development of lethal ventricular arrhythmias in the ischemic heart. In acute myocardial ischemia, adrenergic stimulation of the ischemic myocardium is independent of plasma catecholamines, since local catecholamine concentrations within the ischemic myocardium surpass plasma concentrations by several orders of magnitude. Both afferent and efferent autonomic nerves are activated immediately with myocardial ischemia. Poorly perfused myocardium, however, is protected within the first few minutes of ischemia, via several mechanisms, against high local concentrations of catecholamines. Ischemia-associated metabolic alterations, such as extracellular potassium accumulation, acidosis, and especially the accumulation of adenosine reduce the transmitter release induced by central sympathetic stimulation. Furthermore, the functional neuronal amine reuptake (uptake1) prevents excessive local accumulation of noradrenaline. With progression of myocardial ischemia to more than 10 min local nonexocytotic noradrenaline release prevails. This release is not prevented by the above-mentioned protective mechanisms and accounts for local extracellular catecholamine concentrations in the micromolar range, i.e., 100 to 1000 times higher than the normal plasma concentrations. It shows several features that make it possible to differentiate it from exocytotic release and to assign it to a carrier-mediated transport of noradrenaline from the sympathetic nerve ending into the synaptic cleft. This release is independent of central sympathetic activity, availability of extracellular calcium, activation of both neuronal calcium channels and protein kinase C, and is not accompanied by the release of sympathetic co-transmitters such as neuropeptide Y. It is however suppressed by blockers of uptake1 and by inhibitors of sodium-proton exchange. Depletion of cardiac catecholamine stores by chronic sympathetic denervation effectively suppresses malignant arrhythmias induced by experimental coronary ligature. Accordingly, inhibitors of nonexocytotic noradrenaline release such as uptake1, blocking agents or sodium-proton exchange inhibitors effectively reduce the occurrence of ischemia-associated ventricular fibrillation, emphasizing the relevance of nonexocytotic noradrenaline release in myocardial ischemia. At the postsynaptic side, catecholamines released during myocardial ischemia exert their effects by stimulating alpha- and beta-adrenergic receptors of cardiac myocytes. During acute myocardial ischemia the responsiveness of adrenergic receptors to stimulation by catecholamines is enhanced. Several studies have demonstrated an increase in functionally coupled beta-adrenergic receptor number during myocardial ischemia. Likewise, alpha 1-adrenergic responsivity increases in myocardium subjected to acute ischemia and contributes significantly to the arrhythmogenic effect of catecholamines.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sympatho-adrenergic activation of the ischemic myocardium and its arrhythmogenic impact. 763 99

Platelet thromboxane receptors are acutely and reversibly upregulated after acute myocardial infarction. To determine if platelet thromboxane receptors are under transcriptional control, we isolated and characterized human genomic DNA clones containing the 5' flanking region of the thromboxane receptor gene. The exon-intron structure of the 5' portion of the thromboxane receptor gene was determined initially by comparing the nucleotide sequence of the 5' flanking genomic clone with that of a novel human uterine thromboxane receptor cDNA that extended the mRNA 141 bp further upstream than the previously identified human placental cDNA. A major transcription initiation site was located in three human tissues approximately 560 bp upstream from the translation initiation codon and 380 bp upstream from any previously identified transcription initiation site. The thromboxane receptor gene has neither a TATA nor a CAAT consensus site. Promoter function of the 5' flanking region of the thromboxane receptor gene was evaluated by transfection of thromboxane receptor gene promoter/chloramphenicol acetyltransferase (CAT) chimera plasmids into platelet-like K562 cells. Thromboxane receptor promoter activity, as assessed by CAT expression, was relatively weak but was significantly enhanced by phorbol ester treatment. Functional analysis of 5' deletion constructs in transfected K562 cells and gel mobility shift localized the major phorbol ester-responsive motifs in the thromboxane receptor gene promoter to a cluster of activator protein-2 (AP-2) binding consensus sites located approximately 1.8 kb 5' from the transcription initiation site. These studies are the first to determine the structure and organization of the 5' end of the thromboxane receptor gene and demonstrate that thromboxane receptor gene expression can be regulated by activation of protein kinase C via induction of an AP-2-like nuclear factor binding to upstream promoter elements. These findings strongly suggest that the mechanism for previously described upregulation of platelet thromboxane receptors after acute myocardial infarction is increased thromboxane receptor gene transcription in platelet-progenitor cells.
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PMID:Characterization of 5' end of human thromboxane receptor gene. Organizational analysis and mapping of protein kinase C--responsive elements regulating expression in platelets. 764 19

Ischemic preconditioning has been shown to be one of the most powerful means of protecting the myocardium from ischemic injury in experimental animal models, although the mechanism is incompletely understood. In this review we discuss the evidence for preconditioning occurring in ischemic syndromes in humans, whether the human myocardium can be preconditioned, and whether preconditioning would have a place as a therapeutic tool in clinical practice. Some studies evaluating patients after acute myocardial infarction have shown a better outcome in patients reporting angina before the onset of the infarction, but this is not a universal finding, and it is difficult to exclude other confounding factors, such as collateral flow, from influencing the results. More controlled prospective studies have evaluated patients undergoing percutaneous transluminal coronary angioplasty and have found less ST-segment change and less reported angina during the second balloon inflation when compared with the first. Again, it is impossible to completely exclude other causes for this effect, but the dependence on mechanisms that are known to be important for preconditioning in animal models does suggest the phenomena are the same. Further experiments using isolated human atrial muscle have shown that human myocardium can be preconditioned and that the mechanisms involved are similar to those elucidated in animal models (adenosine, protein kinase C, and ATP-dependent potassium channels). In clinical medicine preconditioning is most likely to benefit patients when it is used to protect against the ischemia induced by cardiac surgery. In this respect, a study has shown that in patients undergoing coronary artery bypass grafts, the reduction in ATP occurring during the first ischemic period is attenuated in those given an ischemic preconditioning protocol beforehand. Despite these advances, it is likely that the full potential of preconditioning in clinical practice will not be realized until the whole mechanism of protection is understood and a safe pharmacological "preconditioning" agent becomes available.
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PMID:Preconditioning the human myocardium: recent advances and aspirations for the development of a new means of cardioprotection in clinical practice. 885 Mar 77

Ischemic preconditioning is a phenomenon in which exposure of the heart to a brief period of ischemia causes it to quickly adapt itself to become resistant to infarction from a subsequent ischemic insult. The mechanism is not fully understood but, at least in the rabbit, it is known to be triggered by occupation of adenosine receptors, opioid receptors, bradykinin receptors and the generation of free radicals during the preconditioning ischemia. All of these are thought to converge on and activate protein kinase C (PKC), which in turn activates a tyrosine kinase. This kinase cascade eventually terminates on some unknown effector, possibly a potassium channel or a cytoskeletal protein, which makes the cells resistant to infarction. If this process can be understood, it should be possible to devise a method for conferring this protection to patients with acute myocardial infarction.
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PMID:Signal transduction in ischemic preconditioning. 933 Jul 17

Diabetes mellitus is one of the diseases with the greatest risk of developing coronary disease (CD), with the estimation of this risk in relation to the general population being from 2 to 4-fold greater. The existence of diabetes worsens the prognosis of CD and thus, postinfarction mortality in these patients is double that observed in non-diabetic patients. Together with the risk factors found in the general population, those of special interest are those derived from diabetes itself, such as hyperglycemia, dyslipemia, coagulation disorders and hyperinsulinemia or insulin resistance. Among these, the most important is probably the hyperglycemia which may contribute to the appearance of CD by different mechanisms such as proteic glycosylation, accumulation of sorbitol, increase in the synthesis of protein kinase C or oxidative stress. It must not be forgotten that an old controversy has recently been brought up suggesting that sulphonylureas may have a certain cardiotoxic effect, probably acting on the potassium channels dependent on ATP. Acute myocardial infarction in diabetic patients carries a greater risk of congestive heart failure, recurrent infarction, arrhythmia and cardiogenic shock, with one of its characteristics being the possibility of being silent when autonomic neuropathy is present. The prognosis of CD may be markedly improved by obtaining optimum glycemic control during the hours following infarction using intensified treatment. Diabetic myocardiopathy as a differentiated nosology responsible for alterations in myocardial contractile function and greater prevalence of heart failure in these patients seems to be clearly demonstrated although its etiology remains unknown.
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PMID:[Heart pathology of extracardiac origin. XI. Cardiac repercussions of diabetes mellitus]. 978 Jul 81

We studied the effect of nickel ions on platelet function because hypernickelemia has been found in patients with acute myocardial infarction. We previously demonstrated that nickel can activate an intracellular pathway leading to cytoskeleton reorganization consequent to tyrosine phosphorylation of p60(src) in human platelets independently of integrin alpha-IIb-beta(3). Moreover, in von Willebrand factor-stimulated platelets, the tyrosine phosphorylation of pp60(c-src) is closely associated with the activation of phosphatidylinositol 3-kinase (PIK), and two adhesion receptors, glycoprotein (Gp)Ib and GpIIb/IIIa(alpha-IIb-beta(3)), are involved. In our study, 1 and 5 mM nickel in the presence of fibrinogen induced platelet aggregation (independently of protein kinase C activation) and secretion. The pretreatment with a PIK inhibitor, wortmannin, strongly decreased nickel-induced platelet aggregation. Platelet treatment with mocarhagin, a cobra venom metalloproteinase that cleaves GpIba, significantly reduced aggregation induced by 5 mM without affecting the response to other agonists such as adenosine diphosphate (ADP). Moreover, nickel caused PIK translocation to the cytoskeleton. Taken together, these observations suggest a partial involvement of both integrins alpha-IIb-beta(3) and GpIb-V-IX complex in Ni(2+)-induced platelet activation.
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PMID:Involvement of the glycoproteic Ib-V-IX complex in nickel-induced platelet activation. 1133 82

Vascular endothelial growth factor (VEGF) is an angiogenic mitogen, specific for endothelial cells. Hypoxia-induced VEGF in endothelial cells and cardiomyocytes leads to autocrine and paracrine stimulation, respectively. During myocardial ischemia, VEGF is upregulated in the endothelium and myocardium, and may mediate angiogenesis. Morphine sulfate is commonly used in pain relief for patients with acute myocardial infarction. We investigated the effect of morphine sulfate on VEGF expression in cultured endothelial cells and cardiac myocytes subjected to hypoxia. Enzyme-linked immunosorbent assays showed that morphine sulfate significantly inhibited hypoxia-induced VEGF expression in mouse heart microvascular endothelial cells (SMHEC4), primary cultures of human umbilical vein endothelial cells (HUVECs) and in primary cultures of rat cardiac myocytes (P<0.05). Real time reverse transcriptase polymerase chain reaction showed that morphine treatment (100 ng/ml) of hypoxic HUVECs resulted in a significant reduction in mRNA levels of VEGF(121) and VEGF(165) isoforms. Transfection of HUVECs with a human VEGF promoter-luciferase construct showed that hypoxia-induced transcriptional activation of VEGF was markedly inhibited by morphine sulfate (P<0.05). Phosphatidyl inositol-3 kinase and protein kinase C-mediated activation of the VEGF promoter was also inhibited by morphine. The opioid antagonist naloxone significantly reversed the inhibitory effects of morphine in endothelial cells suggesting the involvement of opioid receptors. Our results show that the inhibitory effects of morphine on hypoxia-induced VEGF expression in endothelial cells and cardiac myocytes can lead to a decrease in the autocrine and paracrine stimulation and hence limit neovascularization of the ischemic myocardium.
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PMID:Morphine sulfate inhibits hypoxia-induced vascular endothelial growth factor expression in endothelial cells and cardiac myocytes. 1173 63

Reperfusion has the potential to introduce additional injury that is not evident at the end of ischaemia per se, i.e. reperfusion injury. Reperfusion injury is expressed as endothelial and microvascular dysfunction, impaired blood flow, metabolic dysfunction, cellular necrosis, and apoptosis. There is an impressive array of mechanisms contributing to reperfusion injury. Postconditioning, defined as brief periods of reperfusion alternating with re-occlusion applied during the very early minutes of reperfusion, mechanically alters the hydrodynamics of early reperfusion. However, postconditioning also stimulates endogenous mechanisms that attenuate the multiple manifestations of reperfusion injury listed above. These mechanisms include ligands, such as adenosine and opioids, that act as proximal triggers to stimulate molecular pathways involving mediators such as protein kinase C, mitochondrial ATP-sensitive potassium channels, and survival kinases. Postconditioning may also inhibit deleterious pathways such as p38 and JNK mitogen-activated protein (MAP) kinases and attenuate the damage to endothelial cells and cardiomyocytes from oxidants, cytokines, proteases, and inflammatory cells. Postconditioning has been shown to inhibit the mitochondrial permeability transition pore. Hence, postconditioning marshals a variety of endogenous mechanisms that operate at numerous levels and target a broad range of pathological mechanisms. Two clinical studies in patients with acute myocardial infarction have demonstrated that postconditioning was effective in reducing infarct size. Postconditioning indirectly supports the concept of reperfusion injury in animal models of ischaemia-reperfusion and in patients, and exerts cardioprotection that is equivalent to that of ischaemic preconditioning.
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PMID:Postconditioning: reduction of reperfusion-induced injury. 1654 49

It is now recognized that changes occurring during cardiac remodeling may influence the tolerance of the myocardium to ischemic stress. Therefore, the present study investigated the response of the post-infarcted heart to ischemia in an experimental model of ischemia and reperfusion injury and the possible underlying mechanisms. Acute myocardial infarction (AMI) was induced in Wistar male rats by ligating the left coronary artery (AMI, n = 13), while sham-operated rats were used as controls (SHAM, n = 11). At 2 weeks, cardiac dysfunction was observed in AMI, as indicated by the reduction of the left ventricular EF%. Isolated hearts were then subjected to 30 min of zero-flow global ischemia followed by 45 min of reperfusion. Ischemic contracture was significantly depressed in AMI hearts. Postischemic left ventricular end diastolic pressure (LVEDP45) in mmHg and LDH release in IU/g were markedly decreased; LVEDP45 was 52.1 (7.5) for AMI vs 96.6 (7.5),P < 0.05 and LDH release was 7.5 (1.0) in AMI vs 11.4 (0.56) in SHAM, P < 0.05. This response was associated with 2-fold increase in HSP70 expression in AMI hearts (noninfarcted segment), P < 0.05 vs SHAM and 1.7 fold increase in the expression of the phospho-HSP27, P < 0.05, while the expression of PKCepsilon was shown to be 1.4-fold less in AMI, P < 0.05. In conclusion, the post-infarcted heart seems to be resistant to ischemiareperfusion injury and heat shock protein 70 and 27 may be involved in this response.
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PMID:Enhanced tolerance of the rat myocardium to ischemia and reperfusion injury early after acute myocardial infarction. 1728 51


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