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)

There is evidence that cardiac hypertrophy in spontaneously hypertensive rats (SHR) occurs before the development of hypertension. 1,2-Diacylglycerol, which is thought to be a second messenger activating protein kinase C, is also produced in excess in SHR hearts at 4 weeks of age, before established hypertension. We determined myocardial 1,2-diacylglycerol content in SHR with and without prazosin and enalapril from 3 to 4 weeks of age. Hearts from untreated SHR had greater RNA and DNA synthesis and greater relative weights at 4 weeks of age than those from Wistar-Kyoto (WKY) rats. There was no difference in triglyceride content or phospholipid species between WKY rats and untreated SHR, except for a higher cholesterol content in SHR. Treatment of SHR with enalapril, but not prazosin, lowered not only 1,2-diacylglycerol content but also RNA synthesis to the levels of WKY rats. Moreover, fatty acids involved in 1,2-diacylglycerol were altered by enalapril despite the lack of a difference between WKY rats and untreated SHR. Prazosin did not have any effect on 1,2-diacylglycerol fatty acid composition. Enalapril may decrease cardiac hypertrophy in SHR by lowering myocardial 1,2-diacylglycerol production.
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PMID:Enalapril reduces the enhanced 1,2-diacylglycerol content and RNA synthesis in spontaneously hypertensive rat hearts before established hypertension. 138 Oct 46

Both angiotensin II and the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), significantly depressed developed pressure, oxygen consumption, and coronary flow in isolated perfused rat hearts and caused a decrease in diastolic and systolic [Ca2+]i and [Ca2+]i transients. PMA and angiotensin II did not change the levels of cAMP but moderately decreased PCr/Cr. The decrease in systolic [Ca2+]i and amplitude of [Ca2+]i transients caused by PMA and angiotensin II resulted in depressed cardiac function. Hearts perfused with PMA and angiotensin II had a decreased sensitivity to extracellular calcium. Depressed developed pressure and oxygen consumption in the PMA- and angiotensin II-treated hearts may have been due to a decrease in amplitude of effective [Ca2+]i transients, because the [Ca2+]i threshold for cross-bridge interaction was presumably higher than the diastolic [Ca2+]i in these hearts.
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PMID:Angiotensin II and phorbol esters depress cardiac performance and decrease diastolic and systolic [Ca2+]i in isolated perfused rat hearts. 187 56

Phorbol esters reduce cardiac contractility and produce coronary vasoconstriction presumably by stimulating protein kinase C (PKC). We tested whether adenosine altered the response to phorbol 12-myristate 13-acetate (PMA) in isolated rat hearts. Hearts, perfused at constant flow and constant heart rate, were exposed to PMA (10 nM) for 30 min and then allowed 30 min of recovery. PMA reduced left ventricular developed pressure (LVDP) from 81 +/- 2 to 49 +/- 3 and 40 +/- 2 mmHg (51 +/- 3% of baseline LVDP) after 30 min infusion and 30 min recovery, respectively. PMA also increased coronary perfusion pressure to 224 +/- 13% of baseline after 60 min. The PKC inhibitor bisindolylmaleimide (0.5 microM) blocked the PMA-induced negative inotropy and vasoconstriction. Adenosine (100 microM) and the A1-agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 0.1 microM) significantly attenuated the negative inotropic effect of PMA as LVDP was maintained at 81 +/- 4% and 99 +/- 7% of baseline, whereas CGS-21680, an A2-agonist, had no beneficial effect on function (54 +/- 4% of baseline). Adenosine and CGS-21680 (0.1 microM), but not CCPA, significantly attenuated PMA-induced coronary vasoconstriction. These results suggest that adenosine receptor activation may modulate myocardial PKC activity or attenuate the effects of increased PKC activity.
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PMID:Adenosine attenuates phorbol ester-induced negative inotropic and vasoconstrictive effects in rat hearts. 779 15

Using a paced Lagendorff-perfused rabbit heart paradigm, we investigated the role of protein kinase C (PKC) in the development of ventricular fibrillation (VF) in hearts subjected to hypoxia (12 min) and re-oxygenation (40 min). We studied the effect of putative activators and inhibitors of PKC on the incidence of VF. Hearts exposed to 4 beta-phorbol,12,13-dibutyrate (PDBu), isophorbol or the membrane permeant diacylglycerol analog, 1-oleoyl-2-acetyl-rac-glycerol (OAG), during the prehypoxic phase had an increased incidence of VF during the hypoxic and reoxygenation periods. The incidence of VF was 90%, 83% and 75% in hearts exposed to PDBu, isophorbol and OAG, respectively (P < 0.05 vs control). Perfusion of hearts with PDBu was associated with a significant increase in the membrane fraction of cardiac PKC activity. In the presence of the inactive phorbol ester 4 alpha-phorbol didecanoate, the incidence of VF was 17% (P > 0.05 vs control). PKC activators were profibrillatory at concentrations that did not affect cardiac function: neither left ventricular developed pressure nor coronary perfusion pressure were affected. The effect of PDBu was antagonized by staurosporine: the incidence of VF was 17% in PDBu+staurosporine treated hearts (P < 0.05 vs control). To further study the profibrillatory effect of PDBu, hearts were exposed to PDBu in the presence of the ATP-dependent potassium channel antagonist glibenclamide. The latter prevented PDBu-induced VF. The results show that under the conditions employed, PDBu-induced activation of PKC induces redistribution of PKC activity and is associated with the development of VF.
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PMID:Phorbol ester-induced ventricular fibrillation in the Langendorff-perfused rabbit heart: antagonism by staurosporine and glibenclamide. 815 62

Myocardial stretch and the renin-angiotensin system have been implicated in the development of cardiac hypertrophy through the activation of specific target genes. However, the relative importance of these putative hypertrophic stimuli has not been established in vivo. We used an isolated isovolumic heart preparation in which coronary perfusion pressure (CPP), left ventricular end-diastolic pressure, and pharmacological therapy can be independently manipulated to study this relationship. High CPP (140 cmH2O), which increased coronary flow (8.99 vs. 17.6 ml/min) and left ventricular systolic pressure (50 vs. 91 mmHg), increased steady state c-fos mRNA expression 2.3-fold (all P < 0.01 vs. low CPP). In contrast, increased left ventricular end-diastolic pressure (25 mmHg) and/or infusion of angiotensin II in the absence of increased CPP was not associated with an increase in c-fos mRNA expression. The change in c-fos gene expression seen with increased CPP was largely reversed by treatment with an angiotensin type 1 (AT1) receptor blocker. Hearts perfused at high CPP demonstrated increased translocation/activation of protein kinase C-epsilon relative to controls. None of the hearts studied were ischemic during perfusion. Thus, in the perfused adult rat heart, dynamic, but not static, stretch activates the early response gene, c-fos, and may involve the endogenous reninangiotensin system and protein kinase C.
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PMID:Role of endogenous renin-angiotensin system in c-fos activation and PKC-epsilon translocation in adult rat hearts. 876 71

The renin-angiotensin system has been implicated in the hypertrophic adaptation of the heart to exogenous pathological loads, such as hypertension and aortic stenosis; however, the role of this hormonal system in the cardiac adaptations to physiological loads, such as chronic exercise conditioning, has not been established. We therefore studied the effect of angiotensin receptor 1 (AT1) blockade on the chronic cardiac responses of rats subjected to an 8-wk swimming program. Compared with matched sedentary controls, untreated swimmers increased their left ventricular weights by 13%, and swimmers treated with the AT1 antagonist L-158809 increased their left ventricular weights by 11% (both P < 0.05 vs. sedentary controls). The incorporation of labeled amino acids into the heart at the time of death was unchanged in all groups, and therefore the increase in heart weight in both swim-conditioned groups appeared to reflect a decrease in the rate of protein degradation in the heart. Hearts from both swim-conditioned groups manifested an increase in the V1-predominant myosin isoform pattern but not an increase in atrial natriuretic factor mRNA expression or protein kinase C translocation. The fact that these patterns of adaptation are preserved in exercised conditioned animals treated with an AT1 antagonist suggests that the chronic hypertrophic response of the heart to physiological loads is not influenced by the renin-angiotensin system.
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PMID:Angiotensin receptor 1 blockade does not prevent physiological cardiac hypertrophy in the adult rat. 887 51

1. This study examines the protective effect of staurosporine, chelerythrine, Ro 31-8220 and 2,3-butanedione monoxime in rat hearts during hypothermic storage. 2. Hearts were microperfused at 4 degrees C for 24 or 48 h with a storage buffer that in some cases contained one of these protein kinase C inhibitors either alone or in combination with 2,3-butanedione monoxime. After hypothermic storage, hearts were rewarmed to 37 degrees C with Krebs-Henseleit buffer. Cardiac function was then assessed in either Langendorff mode or working heart mode. 3. Compared with values from fresh non-stored hearts, hypothermic stored hearts showed a significant decrease in both coronary flow and left ventricular developed pressure when the stored hearts were reperfused in Langendorff mode. The decrease in coronary flow and left ventricular developed pressure was more pronounced in hearts stored for 48 h than in those stored for 24 h. 4. Hearts stored for 24 or 48 h, with or without the protein kinase C inhibitors, and then perfused in working mode generated less aortic flow and less cardiac output than fresh unstored hearts. 5. Hearts preserved in solutions containing staurosporine, chelerythrine, Ro 31-8220 or 2,3-butanedione monoxime had significantly higher left ventricular developed pressure values on reperfusion than hearts stored without any such drug. 6. Addition of 2,3-butanedione monoxime to a storage buffer containing either staurosporine, chelerythrine or Ro 31-8220 further improved left ventricular developed pressure, aortic flow and cardiac output values in these stored hearts. The group of hearts stored in a buffer containing 2,3-butanedione monoxime and chelerythrine gave the highest left ventricular developed pressure value seen during reperfusion. 7. The ATP and creatine phosphate concentrations of hearts stored in buffer alone were significantly lower than those of fresh unstored hearts, irrespective of the duration of storage. ATP concentrations were better preserved in hearts stored in a buffer containing 2,3-butanedione monoxime or/and one of the protein kinase C antagonists than those stored without such antagonists. A positive correlation was found between peak cardiac output values and the concentrations of combined high-energy phosphates in various groups of stored and reperfused hearts. 8. The present study showed that inhibition of protein kinase C during long-term hypothermic storage significantly increased high-energy phosphate concentrations and also improved contractile function during reperfusion.
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PMID:Effect of protein kinase C inhibitors and 2,3-butanedione monoxime on the long-term hypothermic preservation of isolated rat hearts. 897 11

Our recent studies utilizing an in vivo regional ischemia model revealed no changes in the subcellular distribution of protein kinase C (PKC) in dog and rabbit hearts after repeated 5 min episodes of preconditioning ischemia/reperfusion. However, 10 min of sustained ischemia resulted in an increase in PKC activity in the membrane fraction. These findings indicate that prolonged ischemia may cause changes in the subcellular distribution of PKC. However, the detailed time course of these changes during sustained severe ischemia is poorly resolved. Thus, our objective was to study temporal changes in PKC distribution in the cytosolic, nuclear, and membrane fractions isolated from globally ischemic rabbit heart. Hearts were removed under deep anesthesia, placed into normal saline at 37 degrees C, and repeatedly sampled from apex to base at baseline, 2, 5, and 10 min into global ischemia, with matched samples obtained in every heart. PKC activity was increased at 2 min into global ischemia in both the nuclear fraction (1069 +/- 75 vs. 893 +/- 49 pmol/min/g at baseline; p = 0.05) and the membrane fraction (1374 +/- 95 vs 1187 +/- 59 pmol/min/g at baseline; p < 0.05) with persistent translocation observed at 5 and 10 min into the protocol. Thus, direct biochemical determination of PKC activity in the isolated rabbit heart revealed increased activity in the nuclear and the membrane fractions as early as 2 min into global ischemia.
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PMID:Temporal changes in the subcellular distribution of protein kinase C in rabbit heart during global ischemia. 960 79

Although there is much information on ischaemic preconditioning in the adult myocardium, this phenomenon has not yet been investigated in neonatal hearts. To examine the early development of cardiac tolerance to ischaemia and the possible protective effects of preconditioning, rat hearts isolated on days 1, 4 and 7 of postnatal life were perfused (Langendorff) with Krebs-Henseleit solution at constant pressure, temperature (37 degrees C) and rate (200 beats/min). Developed force (DF) of contraction was measured by an isometric force transducer, and analysed using an on-line computer. Hearts were exposed to 40 or 60 min of global ischaemia followed by 30 min of reperfusion. Preconditioning was induced by three 3-min periods of global ischaemia, each separated by 5-min periods of reperfusion. Developmental changes in expression of protein kinase C (PKC) isoforms, and their activation following preconditioning, were estimated using Western blot analysis. Recovery of contractile function during reperfusion decreased from day 1 (48 +/- 2%) to day 4 (42 +/- 1%) and day 7 (33 +/- 2%). Preconditioning failed to improve ischaemic tolerance on day 1 (46 +/- 2%) and on day 4 (43 +/- 3%), but pronounced effect was observed on day 7 (40 +/- 2%). Prolonging the period of sustained ischaemia from 40 to 60 min on day 1 did not lead to a better recovery of contractile function in preconditioned hearts. PKC isoforms alpha, delta, epsilon and zeta were expressed in the ventricular myocardium during the first week of life, but there was no evidence of translocation following preconditioning on day 7. It may be assumed that the decreasing tolerance of the heart to ischaemia during early postnatal life is counteracted by the development of an endogenous protection.
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PMID:Tolerance to ischaemia and ischaemic preconditioning in neonatal rat heart. 960 35

Heat stress (HS) and the subsequent expression of 72 kDa heat shock protein (HSP 72) has been shown to enhance post-ischemic functional recovery and reduce infarct size. Because the synthesis of heat shock proteins involves activation of heat shock transcription factors through phosphorylation, we hypothesized that inhibition of protein kinase C (PKC) would block HS mediated protection and expression of HSP 72 in the heart. Five groups of rats were studied (1) Sham anesthetized, (2) HS group--animals were heat shocked by raising the whole body core temperature to 42 degrees C for 15 min, (3) Vehicle group--HS rats treated with 50% DMSO in saline, (4) PKC inhibitor-treated group--specific PKC antagonist, chelerythrine chloride (5 mg/kg, i.p) given 30 min prior to HS and (5) Vehicle treated control--non-HS rats treated with vehicle prior to ischemia/reperfusion. Hearts were subjected to 30 min of regional ischemia and 90 min of reperfusion 24 h after HS. Risk area was delineated by injection of 10% Evan's blue and infarct size determined using computer morphometry of tetrazolium stained sections. Infarct size (% area at risk) reduced significantly from 49.4 +/- 2.3% (n = 7) in sham to 10.0 +/- 2.5% (p < 0.01) and 9.1 +/- 3.0% in HS and vehicle treated HS groups respectively (p < 0.05) Treatment with chelerythrine prior to HS increased infarct size to 49.4 +/- 2.3% (p < 0.05). Infarct size in chelerythrine-treated non-HS ischemic/reperfused heart was 40.7 +/- 5.4%, which did not differ significantly from vehicle-treated sham group. Western blot analysis demonstrated marked increase in HSP 72 in HS groups (with or without vehicle treatment) and pretreatment with chelerythrine chloride failed to inhibit the expression of HSP 72. The results suggest that HS-induced ischemic tolerance is mediated via PKC pathway and this protection does not appear to be directly related to the expression of HSP 72 in rat heart.
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PMID:Role of protein kinase C and 72 kDa heat shock protein in ischemic tolerance following heat stress in the rat heart. 1039 76


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