Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151814 (coronary occlusion)
 3,687 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Considerable controversy surrounds the role of protein kinase C (PKC) in ischemic preconditioning (PC). Previous studies have used pharmacological agents and/or measured total myocardial PKC activity; however, no information is available regarding the effects of PC on individual isoforms in vivo. We performed a comprehensive evaluation (using Western immunoblotting) of the expression and subcellular distribution of all 11 currently known PKC isoforms in the heart of conscious rabbits subjected to four different ischemic PC protocols known to induce early and/or late PC (one, three, or six cycles of 4-minute coronary occlusion [4'O]/4-minute reperfusion [4'R]; four cycles of 5-minute occlusion [5'O]/10-minute reperfusion [10'R]). Ten PKC isoforms (alpha, beta1/beta2, gamma, delta, epsilon, zeta, eta, iota, lambda, and mu) were found to be expressed in the rabbit heart. Quantitative immunoblotting demonstrated that as a subgroup, conventional PKCs (cPKCs) are more abundant than novel PKCs (nPKCs) (1445 versus 313 pg PKC/microg tissue protein, respectively) and that PKC alpha is the predominant isoform among the cPKCs (alpha, beta1, beta2, and gamma), representing 51% of this subgroup, and PKC epsilon is the most abundant among the nPKCs (delta, epsilon, zeta, and eta), accounting for 62% of this subgroup. None of the ischemic PC protocols examined caused appreciable changes in total PKC activity, in the subcellular distribution of total PKC activity, or in the subcellular distribution of PKC isoforms alpha, beta1/beta2, gamma, delta, zeta, iota, lambda, and mu. In contrast, all PC protocols caused significant translocation of PKC epsilon and PKC eta isoforms from the cytosolic to the particulate fraction. The particulate fraction of PKC epsilon increased in a dose-dependent fashion with the number of occlusion/reperfusion cycles performed, from 35+/-2% in the control group to 43+/-2% after one 4'O/5-minute reperfusion (5'R) cycle (P<.05), 52+/-2% after three cycles (P<.05 versus one cycle), and 66+/-3% after six cycles (P<.05 versus three cycles). The particulate fraction of PKC epsilon also increased, after four 5'O/10'R cycles, to 50+/-3% (P<.05 versus control). In contrast to PKC epsilon, the translocation of PKC eta was independent of the number of occlusion/reperfusion cycles performed. The particulate fraction of PKC eta increased from 67+/-3% in the control group to 84+/-2% after one 4'O/5'R cycle (P<.05), 84+/-2% after three 4'O/4'R cycles (P<.05), 86+/-3% after six 4'O/4'R cycles (P<.05), and 83+/-2% after four 5'O/10'R cycles (P<.05). When expressed as a percentage of control values, the increases in the particulate fraction of isoform epsilon were greater than those of isoform eta. The effects of 4'O without reperfusion were similar to those of one cycle of 4'O/5'R, indicating that 5'R did not attenuate isoform translocation. This is the first study to demonstrate PKC translocation after ischemic PC in vivo. The results indicate that in the conscious rabbit, ischemic PC causes selective translocation of the epsilon and eta isoforms without demonstrable changes in total myocardial PKC activity, implying that measurements of total PKC activity are not sufficiently sensitive to detect the involvement of PKC in PC. The results are consistent with the concept that the epsilon and eta isozymes play an important role in the genesis of ischemic PC in the conscious rabbit.
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PMID:Ischemic preconditioning induces selective translocation of protein kinase C isoforms epsilon and eta in the heart of conscious rabbits without subcellular redistribution of total protein kinase C activity. 928 43

Brief ischemic episodes confer marked protection against myocardial stunning 1-3 d later (late preconditioning [PC] against stunning). The mechanism of this powerful protective effect is poorly understood. Although protein kinase C (PKC) has been implicated in PC against infarction, it is unknown whether it triggers late PC against stunning. In addition, the entire PKC hypothesis of ischemic PC remains controversial, possibly because the effects of PKC inhibitors on PC protection have not been correlated with their effects on PKC activity and/or translocation in vivo. Thus, conscious rabbits underwent a sequence of six 4-min coronary occlusion (O)/4-min reperfusion (R) cycles for three consecutive days (days 1, 2, and 3). In the control group (group I, n = 7), the recovery of systolic wall thickening after the six O/R cycles was markedly improved on days 2 and 3 compared with day 1, indicating the development of late PC against stunning. Administration of the PKC inhibitor chelerythrine at a dose of 5 mg/kg before the first O on day 1 (group II, n = 10) abrogated the late PC effect against stunning, whereas a 10-fold lower dose (0.5 mg/kg; group III, n = 7) did not. Administration of 5 mg/kg of chelerythrine 10 min after the sixth reperfusion on day 1 (group IV, n = 6) failed to block late PC against stunning. When rabbits were given 5 mg/kg of chelerythrine in the absence of O/R (group V, n = 5), the severity of myocardial stunning 24 h later was not modified. Pretreatment with phorbol 12-myristate 13-acetate (4 microg/kg) on day 1 without ischemia (group VI, n = 11) induced late PC against stunning on day 2 and the magnitude of this effect was equivalent to that observed after ischemic PC. In vehicle-treated rabbits (group VIII, n = 5), the six O/R cycles caused translocation of PKC isoforms epsilon and eta from the cytosolic to the particulate fraction without significant changes in total PKC activity, in the subcellular distribution of total PKC activity, or in the subcellular distribution of the alpha, beta1, beta2, gamma, delta, zeta, iota, lambda, and mu isoforms. The higher dose of chelerythrine (5 mg/kg; group X, n = 5) prevented the translocation of both PKC epsilon and eta induced by ischemic PC, whereas the lower dose (0.5 mg/kg; group XI, n = 5) prevented the translocation of PKC eta but not that of epsilon, indicating that the activation of epsilon is necessary for late PC to occur whereas that of eta is not. To our knowledge, this is the first demonstration that a PKC inhibitor actually prevents the translocation of PKC induced by ischemic PC in vivo, and that this inhibition of PKC translocation results in loss of PC protection. Taken together, the results demonstrate that the mechanism of late PC against myocardial stunning in conscious rabbits involves a PKC-mediated signaling pathway, and implicate epsilon as the specific PKC isoform responsible for the development of this cardioprotective phenomenon.
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PMID:Direct evidence that protein kinase C plays an essential role in the development of late preconditioning against myocardial stunning in conscious rabbits and that epsilon is the isoform involved. 959 74