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)

The influence of the renin-angiotensin system on the control of cell communication was investigated in isolated ventricular cell pairs of adult rats. It was found that angiotensin II (1 microgram/ml) reduced the junctional conductance (gj) by about 55% within 20 s. This effect of angiotensin II was suppressed by DuP 753--an angiotensin receptor blocking agent. Enalapril (1 microgram/ml)--an angiotensin converting enzyme inhibitor--caused an increase in junctional conductance (106%) within 2 min. The effect of enalapril on gj was not related to activation of beta-adrenergic receptors or cAMP-dependent protein kinase. The effect of angiotensin II on gj was suppressed by staurosporine--a potent inhibitor of protein kinase C. This finding indicates that the peptide is changing gj through activation of protein kinase C. The increase in cell coupling caused by enalapril raises the possibility that the antiarrhythmic action of enalapril as well its effect in congestive heart failure are related to an increase in electrical synchronization of cardiac myocytes.
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PMID:The role of the renin-angiotensin system in the control of cell communication in the heart: effects of enalapril and angiotensin II. 128 Jul 22

Hypertension is associated with a rise in arterial pressure and a compensatory increase in cardiac mass, which if not treated effectively, progresses to decompensated congestive heart failure. This decompensation of an initially compensatory hypertrophy has intensified interest in the factors that initiate and maintain the development of cardiac hypertrophy. The potential signals that induce the development of cardiac hypertrophy are grouped as hemodynamic, growth-promoting hormonal, vasoconstriction-promoting hormonal, and genetic factors. Growth-promoting hormones such as insulin and thyroxine appear to play a permissive, but essential, role in the development and maintenance of cardiac hypertrophy. However, changes in cardiac load, both above and below normal, result in parallel changes in cardiac mass, which will return to normal when a normal load is restored. This adaptive response of the myocardium in direct response to elevated and depressed loads demonstrates that cardiac structure, composition, and function are not fixed postneonatal cardiac properties, but instead are regulated dynamically by the cardiocyte loading environment. This adaptive response is subject to modulation by vasoconstriction-promoting hormones and genetic factors. The current thrust in this research area is to elucidate the cellular signals that transduce the physical stimulus for hypertrophy into biochemical events underlying hypertrophic cardiac growth. To remove complex systemic interactions in vivo from the experimental paradigm, several in vitro models have been used to examine three general, but distinct, cellular pathways involving protein kinase C activation, cyclic AMP formation, and increased ion fluxes. Each pathway demonstrated a stimulatory effect on general protein synthesis, which is necessary for growth in all cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Signals for cardiac muscle hypertrophy in hypertension. 171 89

1,2-Diacylglycerol is believed to play an important role in cellular functions through protein kinase C activation, although its role in cardiac functions remains largely unexplored. We determined the level of 1,2-diacylglycerol and its fatty acid composition in heart tissues from Syrian hamsters with hereditary cardiomyopathy (BIO 14.6 strain) during the development of congestive heart failure from 90 days to 240 days of age. The myopathic hamsters had lower contents of triglyceride and of the major phospholipids, phosphatidylcholine, phosphatidylethanolamine and cardiolipin, in the myocardium when compared to normal hamsters, whereas there was no difference in the cholesterol content. No difference in the myocardial 1,2-diacylglycerol content was observed at 90 days of age. On the other hand, 1,2-diacylglycerol contents in myopathic hearts at 160 and 240 days of age were significantly lower by 21% and 52%, respectively, then in age-matched normal hamsters. The oldest hamsters (240-day-old) showed reduced 1,2-diacylglycerol levels in both groups despite an age-related increase in most lipids. The 1,2-diacylglycerol fatty acid composition profile was found to be different from that of other lipids, and there were several differences in the fatty acid composition of 1,2-diacylglycerol between the two groups at 240 days of age. These results indicate that decreased levels of 1,2-diacylglycerol occur concomitantly with congestive heart failure in the myopathic hamsters.
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PMID:Decreased 1,2-diacylglycerol levels in myopathic hamster hearts during the development of heart failure. 194 78

Since chronic congestive heart failure syndromes are associated with both elevated circulating levels of angiotensin II and potentially lethal ventricular tachyarrhythmias, we investigated the effect of angiotensin II on voltage-dependent cardiac Na+ currents. Single-channel Na+ currents in neonatal rat ventricular myocytes were studied using the patch clamp method in the cell-attached mode. Angiotensin II applied outside the patch increased the frequency of opening and rates of activation and inactivation of single-channel Na+ currents within the patch. These effects were mimicked by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and were prevented by prior incubation with TPA. Therefore, we propose that angiotensin II modulates cardiac Na+ currents by a cytoplasmic second messenger, perhaps protein kinase C, and this may predispose toward arrhythmia.
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PMID:Angiotensin II modulates cardiac Na+ channels in neonatal rat. 255 83

1. The signal transduction process mediated by cyclic AMP that leads to the characteristic positive inotropic effect (PIE) in association with a positive lusitropic effect (acceleration of rate of twitch relaxation) has been well established. Relationships between accumulation of cyclic AMP, changes in intracellular Ca2+ transients and the PIE differ, however, depending on the mechanism of particular drugs that affect different steps in the metabolism of cyclic AMP. Selective partial agonists of beta 1-adrenoceptors and inhibitors of phosphodiesterase (PDE) III cause the accumulation of less cyclic AMP for a given PIE than does isoproterenol. In addition, in aequorin-microinjected canine ventricular muscle, selective inhibitors of PDE III, OPC 18790 and Org 9731, produced smaller decreases in the responsiveness of myofilaments to Ca2+ ions than isoproterenol, while a partial agonist of beta 1-adrenoceptors, denopamine, elicits a decrease in Ca2+ responsiveness of the same extent as does isoproterenol. 2. Activation of myocardial alpha 1-adrenoceptors, as well as stimulation of receptors for endothelin and angiotensin II, which accelerates hydrolysis of phosphoinositide (PI) to result in production of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) are associated with very similar inotropic regulation: (1) the dependence on the species of animals of induction of the PIE; (2) an excellent correlation between the extent of acceleration of hydrolysis of PI and the PIE; (3) isometric contraction curves associated with a negative lusitropic effect; (4) the PIE associated with increases in myofibrillar responsiveness to Ca2+ ions; and (5) the selective inhibition of the PIE by an activator of protein kinase C (PKC), phorbol 12,13-dibutyrate (PDBu), with little effect on the PIE of isoproterenol and Bay k 8644. 3. A novel class of cardiotonic agents, namely, Ca2+ sensitizers such as EMD 53998 and Org 30029, act on the Ca(2+)-binding site of troponin C, increasing the affinity of these sites for Ca2+ ions, or at the actin-myosin interface to facilitate the cycling of cross-bridges. These agents produce a PIE with little change or decrease in Ca2+ transients and may bring about a significant breakthrough in the development of drugs for reversal of myocardial failure in the treatment of congestive heart failure.
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PMID:The effects of various drugs on the myocardial inotropic response. 771 48

This study examined the potential role of ET-1 and the contribution of protein kinase C (PKC) in the desensitization of the ET-1 transmembrane signaling pathway in the left circumflex coronary artery (CCA) of a dog model of congestive heart failure (CHF). In the CCA of the rapid ventricular pacing-overdrive dog model of CHF, elevated plasma endothelin levels were associated with a decrease in the basal accumulation of inositol phosphates and ET-1 mediated activation of phosphatidylinositol (PI) turnover (P < 0.05). To assess whether elevated plasma ET-1 levels may have contributed to the diminished ET-1 responsiveness in the heart failure dogs, ET-1 generation of inositol phosphates was measured following a one hour pretreatment of normal coronary artery rings with 0.1 nM ET-1. As compared to non-treated rings, ET-1 pretreatment resulted in a 33% decrease of ET-1 (10 nM) production of inositol phosphates. To evaluate the role of PKC in this process, normal coronary rings pretreated for a period of one hour with the phorbol ester, phorbol 12-myristate 13-acetate (PMA, 1 microM), resulted in a similar attenuation (36%) of ET-1 production of inositol phosphates. In the presence of the protein kinase C inhibitor staurosporine, both the agonist and phorbol ester induced decreases in ET-1 mediated PI turnover were reversed. Staurosporine even potentiated (75%) ET-1 induced PI turnover despite ET-1 and PMA pretreatments. These results suggest that agonist-induced desensitization of ET-1 mediated PI turnover can occur and is at least one of the possible mechanisms contributing to the desensitization of the ET-1 transmembrane signaling pathway in the pacing-overdrive model of heart failure in the dog.
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PMID:Regulation of the endothelin-1 transmembrane signaling pathway: the potential role of agonist-induced desensitization in the coronary artery of the rapid ventricular pacing-overdrive dog model of heart failure. 826 60

The adequate biological function of the renin-angiotensin system in blood pressure regulation and volume control involves additional factors for a fully balanced response. This includes arachidonic acid-derived lipid mediators, the eicosanoids. Angiotensin II (Ang II) causes (AT1)-receptor mediated stimulation of phospholipase C, resulting in generation of IP3 (inositol triphosphate) and activation of protein kinase C, elevated cytosolic Ca+ and stimulation phospholipase A2. These processes culminate in the generation of cell-specific eicosanoids and their autocrine action on the generating cell or paracrine effects on cells in the vicinity. In vascular tissue, liberated arachidonic acid is mainly converted into vasodilator prostaglandins, i.e. prostacyclin (PGI2) and PGE2. These prostaglandins may attenuate any direct Ang II-induced vasoconstriction, lower systemic vascular resistance and stimulate renal sodium excretion. In some vessels, arachidonic acid released by Ang II may also be converted to vasoconstrictor eicosanoids, i.e. thromboxane A2, PGF2 alpha and 12-HETE. The biological significance of endogenous eicosanoid generation becomes evident if vasoactive eicosanoids become limiting factors for maintaining homoiostasis, i.e. in the fetal circulation, Bartter's syndrome and congestive heart failure where vasodilating eicosanoids (PGE2, PGI2) are involved in maintenance of low vascular resistance and reduced or absent vasoconstriction by Ang II. Vasoconstrictor eicosanoids (thromboxane A2, PGF2 alpha, 12-HETE) contribute to high blood pressure in (renovascular) hypertension and pregnancy-induced hypertension. Alternatively, generation of vasodilator prostaglandins may be reduced in these situations. The vascular renin-angiotensin system is subject to the action of a number of drugs and chemicals, most notably specific inhibitors of the angiotensin-converging enzyme and drugs affecting kidney function (furosemide) and/or vessel tone (propranolol).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostaglandin-mediated actions of the renin-angiotensin system. 849 70

In most mammalian species, activation of myocardial endothelin as well as alpha1-adrenergic and angiotensin receptors leads to an increase in contractile function and myocardial cell hypertrophy, in association with acceleration of PI hydrolysis and with resultant production of IP3 and diacylglycerol. Therefore, these receptors may share a common intracellular signal transduction process in cardiac regulation. Although the pathophysiological relevance of endothelin- and angiotensin-mediated signal transduction has been postulated to play a key role in the progress of congestive heart failure, the details of the regulation are still controversial. We carried out experiments to further study the regulation induced by activation of these receptors. In spite of a wide range of species-dependent variation among mammals in the induction of the cardiotonic effect via these receptors, there is an excellent correlation between the extent of acceleration of PI hydrolysis and the positive inotropic effect (associated with a negative lusitropic effect) of the respective receptor agonists under most experimental conditions in rabbit ventricular myocardium. In isolated rabbit ventricular cardiomyocytes loaded with indo-1/AM, activation of these receptors elicited a very similar changes in the relationship between [Ca2+]i and cell shortening: the [Ca2+]i-shortening trajectory was shifted mainly upwards and the relationship of peak shortening vs peak [Ca2+]i was shifted to the left, an indication that the PIE of these agonists is consistently associated with an increase in [Ca2+]i and in the sensitivity of myofilaments to Ca2+ ions under the same experimental condition. Pieces of evidence in biochemical and pharmacological analyses imply that the products of PI hydrolysis, namely diacylglycerol and subsequent activation of protein kinase C, might play a crucial role in the regulation of cardiac function that is induced upon activation of endothelin, angiotensin and alpha-adrenergic receptors in the rabbit ventricular myocardium.
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PMID:Effects of endothelin-1 on [Ca2+]i-shortening trajectory and Ca2+ sensitivity in rabbit single ventricular cardiomyocytes loaded with indo-1/AM: comparison with the effects of phenylephrine and angiotensin II. 895 60

The clinical features of 106 patients of Takayasu arteritis (TA) seen over a period of 16 years are documented (65 females and 41 males). The mean age was 27.3 +/- 9.2 years. Hypertension was the commonest mode of presentation (51.3%) and was detected in 82 patients (77.4%) at the time of presentation. Vascular bruits were heard in 72 patients (67.9%) and 13 patients (12.3%) were in congestive heart failure. Aortography was performed in 95 patients. Based on the extent of involvement, Type I (branches of aortic arch) was seen in 7 (6.6%) patients, Type II (aortic arch, its branches and descending thoracic aorta) in 7 (6.6%) patients, Type III (descending thoracic aorta and abdominal aorta) in 4 (3.8%) patients, Type IV (abdominal aorta only) in 29 (27.3%) patients and Type V (aortic arch, descending thoracic aorta and abdominal aorta) in 59 (55.7%) patients. Therapeutic modalities included antihypertensive drug therapy in 81 patients, antitubercular drugs in 8 patients, steroids in 16 patients and cyclophosphamide in one patient. Response to steroids was satisfactory in 5 of these 16 patients while the lesions of vasculitis healed in the patient who was treated with cyclophosphamide. Surgical interventions included nephrectomy and autotransplantation of kidney in 3 patients each and revascularization in 4 patients and angioplasty in 4 patients. In the area of pathogenesis of this disease, a high activity of protein kinase C(PKC), an increased intracellular calcium and inositol 1,4,5 triphosphate in both unstimulated and stimulated T cells of TA was observed. These findings suggest an activation of PKC-calcium pathway in TA.
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PMID:Current status of Takayasu arteritis in India. 911 12

The critical cell signals that trigger cardiac hypertrophy and regulate the transition to heart failure are not known. To determine the role of Galphaq-mediated signaling pathways in these events, transgenic mice were constructed that overexpressed wild-type Galphaq in the heart using the alpha-myosin heavy chain promoter. Two-fold overexpression of Galphaq showed no detectable effects, whereas 4-fold overexpression resulted in increased heart weight and myocyte size along with marked increases in atrial naturietic factor ( approximately 55-fold), beta-myosin heavy chain ( approximately 8-fold), and alpha-skeletal actin ( approximately 8-fold) expression, and decreased ( approximately 3-fold) beta-adrenergic receptor-stimulated adenylyl cyclase activity. All of these signals have been considered markers of hypertrophy or failure in other experimental systems or human heart failure. Echocardiography and in vivo cardiac hemodynamic studies indeed revealed impaired intrinsic contractility manifested as decreased fractional shortening (19 +/- 2% vs. 41 +/- 3%), dP/dt max, a negative force-frequency response, an altered Starling relationship, and blunted contractile responses to the beta-adrenergic agonist dobutamine. At higher levels of Galphaq overexpression, frank cardiac decompensation occurred in 3 of 6 animals with development of biventricular failure, pulmonary congestion, and death. The element within the pathway that appeared to be critical for these events was activation of protein kinase Cepsilon. Interestingly, mitogen-activated protein kinase, which is postulated by some to be important in the hypertrophy program, was not activated. The Galphaq overexpressor exhibits a biochemical and physiologic phenotype resembling both the compensated and decompensated phases of human cardiac hypertrophy and suggests a common mechanism for their pathogenesis.
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PMID:Transgenic Galphaq overexpression induces cardiac contractile failure in mice. 922 25


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