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 myocardial infarction, adrenergic stimulation of the heart is thought to cause cell damage and malignant arrhythmias. In rat hearts as well as in human cardiac tissue, ischemia induces norepinephrine (NE) release, which results in micromolar catecholamine concentrations in the interstitial space of the ischemic myocardium. It has been found that local metabolic, rather than centrally evoked NE release, plays the crucial role in excess adrenergic activation of the ischemic myocardium. NE release in ischemia is nonexocytotic and has been characterized as a two-step process. (a) Induced by energy deficiency, NE escapes from its storage vesicles and accumulates in the axoplasm. (b) NE is transported across the plasma membrane into the extracellular space via the neuronal NE carrier (uptake1), which has reversed its normal transport direction because of increased intracellular sodium concentration. NE release induced by ischemia is independent of the presence of calcium in the extracellular space and is not altered by blockade of N-type (neuronal) calcium channels. Furthermore, modulation of protein kinase C does not interfere with NE liberation in the ischemic myocardium. This independence of extracellular calcium, calcium entry into the neuron, and protein kinase C activity is in contrast to the strong calcium dependence of exocytotic transmitter release, which is found under physiological conditions. On the basis of these findings, it was unexpected that calcium antagonists such as gallopamil, verapamil, diltiazem, felodipine, and nifedipine suppress ischemia-induced NE release. The most potent effect was found for gallopamil with a concentration of 50% inhibition (IC50) of 300 nmol/L.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcium antagonism and norepinephrine release in myocardial ischemia. 128 51

Evidence obtained from experimental animals and man indicates that reentry is a major mechanism underlying arrhythmogenesis. However, focal or nonreentrant mechanisms also appear to be operative under a wide variety of pathophysiologic conditions. For example, results obtained using three-dimensional (3D) mapping from 232 simultaneous sites in the feline heart in vivo revealed that nonreentrant or focal mechanisms were prominent during both ischemia and reperfusion. During early ischemia, nonreentrant mechanisms were responsible for initiation of ventricular tachycardia (VT) in 25% of cases and, in cases where VT was initiated by reentry, it often could be maintained by a nonreentrant mechanism. During reperfusion of ischemic myocardium, nonreentrant mechanisms were responsible for initiation of VT in 75% of cases. Most importantly, the transition from VT to ventricular fibrillation in response to reperfusion was secondary to acceleration of a nonreentrant mechanism in either the subendocardium or subepicardium. Potential cellular mechanisms include: 1) sarcolemmal accumulation of amphiphiles such as long-chain acylcarnitines and lysophosphatidylcholine; 2) alpha- and beta-adrenergic mediated effects of catecholamines on the transient inward current (ITI) secondary to an increase in intracellular Ca2+; and 3) alpha-adrenergic receptor-induced decrease in IK mediated by activation of protein kinase C. Recent findings obtained using 3D intraoperative mapping in patients with refractory VT and a previous myocardial infarction also indicate that both reentrant and nonreentrant or focal mechanisms contribute. For example, in 13 selected patients, mapping was of a sufficient resolution to define the mechanisms of 10 runs of VT. Intraoperative mapping indicated that five runs of VT were initiated by intramural reentry, whereas five runs of VT were initiated by a focal or nonreentrant mechanism. The mechanisms underlying ventricular arrhythmias associated with ischemic cardiomyopathy have recently been delineated in dogs after multiple sequential intracoronary embolizations with microspheres (with a decrease in mean ejection fraction from 64% to 25%). Spontaneous VT initiated by focal mechanisms from the subendocardium in 82% and epicardium in 18%, with no evidence of macroreentry. Thus, in divergent pathophysiologic settings, nonreentrant mechanisms appear to contribute importantly to the genesis of lethal ventricular arrhythmias, suggesting that development of novel therapeutic approaches should be directed at inhibition of not only reentrant circuits, but also nonreentrant mechanisms, including triggered activity.
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PMID:The contribution of nonreentrant mechanisms to malignant ventricular arrhythmias. 129 6

Myocardial hypertrophy is the common endpoint of many cardiovascular stimuli such as hypertension, myocardial infarction, valvular disease, and congestive failure. Catecholamines have long been implicated in the pathogenesis of myocardial hypertrophy, however, it is very difficult to sort out catecholamine mechanisms in vivo. We have developed a cell-culture model which excludes hemodynamic effects and allows the assignment of receptor specificity to catecholamine effects. Utilizing this system, we have shown that stimulation of the alpha 1 adrenergic receptor leads to the development of myocardial hypertrophy and results in the selective up-regulation of the fetal/neonatal mRNAs encoding skeletal alpha-actin and beta-MHC, a pattern similar to that seen with hypertrophy in-vivo. Utilizing a co-transfection assay, we have also obtained data that suggest that the beta-PKC isozyme is in a pathway regulating transcription of the beta-MHC isogene. Beta adrenergic stimulation of the cultured cardiac myocytes also results in a modest degree of hypertrophy, however, this effect may be dependent upon myocyte contractile activity and may involve, at least in part, the non-muscle cells present in the culture system.
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PMID:Sympathetic modulation of the cardiac myocyte phenotype: studies with a cell-culture model of myocardial hypertrophy. 133 64

We have proposed that ischemic preconditioning in the rabbit heart is initiated by adenosine A1 receptor stimulation which results in an upregulation of protein kinase C (PKC). Subsequent sustained ischemia then causes renewed stimulation of adenosine A1 receptors with rapid reactivation of PKC and phosphorylation of a target protein(s) which mediates the protection. If the above theory is correct then angiotensin II (AII) receptor stimulation, which is known to activate PKC, should also protect the heart. Isolated rabbit hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was determined by tetrazolium staining. Pretreating hearts with 100 mM AII for 5 min, followed by 10 min of drug-free perfusion prior to the prolonged ischemia limited infarction (7.2 +/- 2.0% of the risk area v 31.1 +/- 3.4% in control animals, P < 0.01). This protection could be blocked by the AT1 receptor blocker losartan (10 microM), but not by the AT2 receptor blocker PD 123319 (10 microM). Polymyxin B (50 microM), a PKC inhibitor, also blocked the protective effect of AII. These observations demonstrated that activation of PKC by AT1 receptor stimulation prior to ischemia does mimic ischemic preconditioning. Following AII infusion, administration, during the 30 min ischemic period, of either SPT [8-(p-sulfophenyl)theophylline] (an adenosine receptor blocker) or losartan failed to block AII's protective effect. However, co-administration of SPT and losartan did abort AII's protection suggesting that AII may not be completely washed out during the 10 min drug-free perfusion allowing residual agonist to reactivate PKC during the 30 min ischemia even when adenosine receptors are blocked. Thus, if only one of the receptors (AT1 or adenosine) were activated during the ischemic period, protection would occur. We conclude that activation of PKC by AII, prior to ischemia, can limit myocardial infarction. While PKC must be reactivated during ischemia to realize protection, the specific receptor type initiating reactivation is not crucial.
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PMID:Pretreatment with angiotensin II activates protein kinase C and limits myocardial infarction in isolated rabbit hearts. 760 6

Regulations of the increase in intracellular Ca2+ concentration ([Ca2+]i) and inositol 1,4,5-trisphosphate (IP3) production by increasing intracellular cyclic AMP (cAMP) levels or activating protein kinase C (PKC) were studied in rat frontocortical cultured neurons. Amitriptyline (AMI; 1 mM), a tricyclic antidepressant, and bradykinin (BK; 1 microM) stimulated IP3 production and caused transient [Ca2+]i increases. Pretreatment with forskolin (100 microM, 15 min) decreased the AMI- and BK-induced [Ca2+]i increases by 33 and 48%, respectively. However, this treatment had no effect on the AMI- and BK-induced IP3 productions. Dibutyryl-cAMP (2 mM, 15 min) also decreased the AMI- and BK-induced [Ca2+]i increases by 23 and 47%, respectively. H-8 (30 microM), an inhibitor of protein kinase A (PKA), attenuated the ability of forskolin to inhibit the AMI- and BK-induced [Ca2+]i increases, suggesting that the activation of cAMP/PKA was involved in these inhibitory effects of forskolin. On the other hand, forskolin treatment had no effect on 20 mM caffeine-, 10 microM glutamate-, or 50 mM K(+)-induced [Ca2+]i increases. Pretreatment with phorbol 12-myristate 13-acetate (PMA; 100 nM, 90 min) decreased both the AMI-induced [Ca2+]i increases and the IP3 production by 31 and 25%, respectively. H-7 (200 microM), an inhibitor of PKC, inhibited the ability of PMA to attenuate the [Ca2+]i increases. PMA also inhibited the BK-induced IP3 production and the [Ca2+]i increases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Forskolin and phorbol myristate acetate inhibit intracellular Ca2+ mobilization induced by amitriptyline and bradykinin in rat frontocortical neurons. 769 65

5-Fluorouracil (5-FU) is a commonly employed chemotherapeutic agent. Among the various toxicities associated with 5-FU, cardiovascular toxicity, consisting principally of acute myocardial ischemia and/or myocardial infarction, has been reported in up to 8.5% of patients treated with this drug. While 5-FU-induced coronary vasospasm has been considered as a potential basis for such clinical toxicity, this hypothesis remains unsubstantiated by laboratory investigation. Accordingly, the present study was designed to investigate the hypothesis that 5-FU induces reversible vasoconstriction of vascular smooth muscle and to study the cellular mechanisms of such vasomotor alterations. To investigate the effects of 5-FU on the vasoreactivity of vascular smooth muscle, 479 exposures were performed in 105 rings of aorta freshly isolated from 23 New Zealand white rabbits. Vasoconstriction was documented in 20 of 86 (23%) rings exposed to 5-FU at 7 x 10(-5) M, 45 of 83 (54%) rings exposed to 5-FU at 7 x 10(-4) M, and 41 of 49 (84%) rings exposed to 5-FU at 7 x 10(-3) M. In each case, 5-FU-induced vasoconstriction was endothelium independent. Pretreatment of rings with 10(-9) M staurosporine, a protein kinase C (PK-C) inhibitor, reduced 5-FU-induced vasoconstriction from 25.0 +/- 6.5 to 2.5 +/- 1.7 mg; staurosporine at a concentration of 10(-8) M abolished 5-FU-induced vasoconstriction. Pretreatment of rings with 10(-7) M phorbol-12,13-dibutyrate, an activator of PK-C, increased the magnitude of 5-FU-induced vasoconstriction 23-fold, from 49.7 +/- 11.1 mg before to 1163.6 +/- 276.4 mg after phorbol-12,13-dibutyrate (P = 0.0002). Neomycin, an inhibitor of phosphoinositide turnover, did not alter the magnitude of 5-FU-induced vasoconstriction. Membrane receptor blockers, including the alpha-adrenergic receptor blocker phentolamine, the beta-adrenergic receptor blocker propranolol, the H1 receptor inhibitor diphenhydramine, the H2 receptor inhibitor cimetidine, the Ca2+ channel blockers verapamil and diltiazem, and the cyclooxygenase inhibitor indomethacin all failed to alter the magnitude of 5-FU-induced vasoconstriction. Furthermore, the 5-FU-related compounds uracil and floxuridine did not produce vasoconstriction. Finally, 5-FU-induced vasoconstriction was abolished by nitroglycerin. These results indicate that (a) 5-FU causes direct, endothelium-independent vasoconstriction of vascular smooth muscle in vitro, (b) this vasomotor response involves activation of PK-C, and (c) this response is independent of vasoactive cell membrane receptors, phosphoinositide turnover, or activation of the cyclooxygenase pathway.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle. 839 84

Cardiac fibroblasts appear to be important in producing and maintaining the extracellular matrix (ECM) of the heart. The abnormal proliferation of cardiac fibroblasts and deposition of the ECM protein, collagen, associated with hypertension and myocardial infarction, may adversely affect the performance of the heart. Several groups of factors affect collagen gene expression and/or growth of cardiac fibroblasts. Angiotensin II, aldosterone and endothelins play a central role in the remodeling of the ECM in hypertension, and decrease collagenase activity and/or increase collagen synthesis in cultured cells. Regulatory peptides that are generally elevated at sites of injury, such as TGF-beta 1 and PDGF, increase collagen synthesis and/or stimulate mitogenesis. Mechanical stretch enhances collagen expression and cell proliferation, responses which could in part be due to integrin activation. Cytokines may stimulate or inhibit cell growth, the latter through prostaglandin formation. Angiotensin II is a principal determinant in vivo of cardiac fibroplasia and synthesis of the ECM proteins, collagen and fibronectin. Cardiac fibroblasts possess G-protein-coupled AT1 receptors for angiotensin II that couple to activation of multiple signalling pathways, including: phospholipase C-beta, with the subsequent release of Ca2+ from intracellular stores and activation of protein kinase C, mitogen-activated protein kinases, tyrosine kinases, phospholipase D, phosphatidic acid formation, and the STAT family of transcription factors. Cardiac fibroblasts respond to angiotensin II with hyperplastic/hypertrophic growth, and increased expression of collagen, fibronectin, and integrins. The mechanisms by which the AT1 receptor activates multiple signalling pathways are not known, although the receptor might interact at some level with both integrins and cytokine receptors. Different signalling pathways of the AT1 receptor may subserve different cellular responses, such as mitogenesis, ECM synthesis, or an inflammatory/stress response. Crosstalk among the signalling pathways of the AT1 receptor, and those of G-protein, cytokine, and growth-factor receptors, may determine the ultimate response of the cell.
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PMID:Molecular signalling mechanisms controlling growth and function of cardiac fibroblasts. 857 2

Ischemic preconditioning signals through protein kinase C (PKC) to protect against myocardial infarction. This protection is characterized by diminished intracellular acidification. Acidification is also a feature of apoptosis, and several agents act to prevent apoptosis by preventing acidification through activation of ion channels and pumps to promote cytoplasmic alkalinization. We characterized metabolic inhibition, recovery, and preconditioning through a PKC-dependent pathway in cardiomyocytes isolated from adult rabbit hearts. Preconditioning reduced loss of viability assessed by morphology and reduced DNA nicking. Blockade of the vacuolar proton ATPase (VPATPase) prevented the effect of preconditioning to reduce metabolic inhibition-induced acidosis, loss of viability, and DNA nicking. The beneficial effect of Na+/H+ exchange inhibition, which is thought to be effective through reduced intracellular Na+ and Ca++, was also abrogated by VPATPase blockade, suggesting that acidification even in the absence of Na+/H+ exchange may lead to cell death. We conclude that a target of PKC in mediating preconditioning is activation of the VPATPase with resultant attenuation of intracellular acidification during metabolic inhibition. Inhibition of the "death protease," interleukin-1-beta converting enzyme or related enzymes, also protected against the injury that followed metabolic inhibition. This observation, coupled with the detection of DNA nicking in cells subjected to metabolic inhibition, suggests that apoptotic cell death may be preventable in this model of ischemia/reperfusion injury.
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PMID:Preconditioning rabbit cardiomyocytes: role of pH, vacuolar proton ATPase, and apoptosis. 863 21

Short periods of ischemia render the myocardium more resistant to a subsequent prolonged coronary occlusion resulting in a reduction of infarct size. This cardioprotective mechanism has been called ischemic preconditioning. Acute myocardial ischemia results in a rapid decline of high energy phosphates. After short periods of ischemia the high energy phosphate levels are better preserved and the increase of lactate is slower during the prolonged subsequent ischemia in the preconditioned group compared to control. The duration of ischemia needed for induction of the protective effect is 2.5 min in dogs and 20 min in our swine model. In porcine myocardium the protection is lost about 1 h after induction and a renewal is not possible at that time, but is 24 h later. For rabbits or dogs, but not in pigs, a late protection 24 h after induction or preconditioning has been shown ("second window of protection"). Adenosine or adenosine A1 receptor agonists, muscarinic M2 receptor agonists, alpha 1-receptor agonists and bradykinin B2 receptor agonists as well as opening of the K+ATP-channel substitute for ischemia in the induction of protection. Activation of protein kinase C results in protection in rats and rabbits, but not in dogs or pigs. Inhibition of protein kinase C translocation or kinase activity results in a loss of the protection induced by preceding ischemia. After blockade of the K+ATP-channel the protection induced by adenosine A1 receptor activation is lost. Therefore opening of the K+ATP-channel is a prerequisite for induction of the protective effect. Inhibition of the inhibitory G-protein by pertussis toxin has been shown to result in a loss of protection, therefore the Gi-protein seems to be involved in the evolution of protection. In humans during coronary angioplasty anginal pain and lactate production during a second balloon occlusion is diminished without any change in the regional myocardial perfusion. This adaptation is inhibited by blockade of the K+ATP-channel or of the adenosine A1 receptor. Intermittent cross-clamping before a longer occlusion during open-heart surgery results in a better preservation of high energy phosphates compared to controls without preceding short ischemia. These observations support the hypothesis that ischemic preconditioning also occurs in humans. Angina pectoris preceding the myocardial infarction may have preconditioned the human heart against the subsequent myocardial infarction, but studies concerning the influence of angina pectoris on short-term outcome after thrombolysis are conflicting. In the future, ischemic preconditioning or preconditioning with drugs may prolong the duration of ischemia tolerated without necrosis and improve the prognosis of patients by reducing the infarct size.
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PMID:-Myocardial protection by preconditioning. Experimental and clinical significance-. 865 Sep 86

To examine the cardioprotective role of A3 adenosine receptors during myocardial ischemia/reperfusion injury, we tested the effect of N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA), a potent and selective A3 adenosine receptor agonist, in models of myocardial stunning and infarction in chronically instrumented conscious rabbits. In phase I (studies of myocardial stunning), rabbits were subjected to six 4-minute coronary occlusions, each separated by 4-minute reperfusion periods, after which the recovery of systolic wall thickening was measured (ultrasonic crystals). In phase II (studies of myocardial infarction), rabbits were subjected to a 30-minute coronary occlusion followed by 3 days of reperfusion. In both phases, IB-MECA was administered as an intravenous bolus (100 micrograms/kg) 10 minutes before the first coronary occlusion. This dose of IB-MECA was determined in pilot studies to have no effect on heart rate, arterial blood pressure, or plasma histamine concentration in rabbits. In phase I, IB-MECA markedly improved the recovery of wall thickening after the six occlusion/reperfusion cycles, and this effect was sustained throughout the 5-hour observation period; the total deficit of wall thickening (a measure of the overall severity of myocardial stunning) was reduced by 68% (control, 129 +/- 16 arbitrary units, n = 7; IB-MECA, 41 +/- 6 arbitrary units, n = 6; P < .01). The protective effects of IB-MECA against stunning were completely blocked by pretreatment with the nonselective adenosine receptor antagonist 8-p-sulfophenyl theophylline or the specific protein kinase C inhibitor chelerythrine. In phase II, IB-MECA reduced myocardial infarct size by 61%; infarct size (tetrazolium staining) was 41 +/- 4% of the risk region in control animals (n = 8) and 16 +/- 6% in IB-MECA-treated animals (n = 8, P < .01). These results demonstrate that in conscious rabbits the A3 adenosine receptor agonist IB-MECA confers a powerful protection against both reversible (stunning) and irreversible (infarction) injury during acute myocardial ischemia and reperfusion by a protein kinase C-mediated pathway, suggesting that selective activation of A3 receptors is an effective means of protecting the ischemic myocardium without hemodynamic changes.
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PMID:Selective activation of A3 adenosine receptors with N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide protects against myocardial stunning and infarction without hemodynamic changes in conscious rabbits. 916 82


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