PKC delta Peptide Activator exerts anti-inflammation and cardio-protective effects
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Apr 16, 2015
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Abstract
Ischemia followed by reperfusion (I/R) causes additional cell injury. Reperfusion injury is initiated by vascular endothelial dysfunction and/or oxidative stress, which is further augmented by leukocytes (i.e., polymorphonuclear leukocyte [PMN]) activation and recruitment. Protein kinase C (PKC) is a key signaling molecule mediating reperfusion injury. The role of PKC delta (d) isoform in myocardial I/R injury is still being debated. In this study, we tested the effects of PKC d peptide activator (PKC d+) on inflammation and PMN-induced postreperfused cardiac function. We found that PKC d+ significantly reduced phorbol-12-myristate-13-acetate (PMA, 15 nM)-induced superoxide (SO) release in isolated rat PMNs. Furthermore, PKC d+ (5 and 10 mM, both n = 5) dose-dependently decreased NG-nitro-L-arginine methyl ester (L-NAME)-induced leukocyte-endothelial interactions in rat mesenteric microcirculation in vivo by intravital microscopy. Lastly, we tested the effects of PKC d+ on I/R+PMNs-induced postreperfused cardiac dysfunction in isolated perfused rat hearts. We found that PKC d+ (10 mM, n = 6) significantly attenuated PMN-induced cardiac dysfunction as compared with control I/R+PMNs hearts (n = 10) in left ventricular developed pressure (LVDP), end diastolic pressure (EDP), and the maximal rate of LVDP (+dP/dtmax; all P<0.05). We also found that PKC d+ treated postreperfused heart tissue showed significantly lower leukocyte vascular adherence and tissue infiltration. These results suggest that PKC d+ attenuated PMN-induced post I/R cardiac contractile and diastolic dysfunction, possibly by inhibiting leukocyte-endothelial interactions and attenuating PMN SO release.
Article Details
How to Cite
CHEN, Qian.
PKC delta Peptide Activator exerts anti-inflammation and cardio-protective effects.
Medical Research Archives, [S.l.], n. 2, apr. 2015.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/62>. Date accessed: 22 dec. 2024.
Keywords
Ischemia/reperfusion injury, PKC delta isoform, Superoxide, Leukocyte-endothelial interactions, Cardiac function
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Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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Chen, C., B. Rueter, S. Krass, C. Zambrano, S. Thomas, C. Prince, B. Bell, V. Chai, J. Emrich and L. H. Young (2010). "The potential clinical application of protein kinase C beta II peptide inhibitor or Gö 6983 in vascular endothelial dysfunction." Curr Top Pharmacol 14: 11-24.( http://www.researchtrends.net/tia/abstract.asp?in=0&vn=14&tid=11&aid=3050&pub=2010&type=)
Chen, L., H. Hahn, G. Wu, C. H. Chen, T. Liron, D. Schechtman, G. Cavallaro, L. Banci, Y. Guo, R. Bolli, G. W. Dorn, 2nd and D. Mochly-Rosen (2001). "Opposing cardioprotective actions and parallel hypertrophic effects of delta PKC and epsilon PKC." Proc Natl Acad Sci U S A 98(20): 11114-11119. (http://www.ncbi.nlm.nih.gov/pubmed/11553773)
Churchill, E., G. Budas, A. Vallentin, T. Koyanagi and D. Mochly-Rosen (2008). "PKC isozymes in chronic cardiac disease: possible therapeutic targets?" Annu Rev Pharmacol Toxicol 48: 569-599. (http://www.ncbi.nlm.nih.gov/pubmed/17919087)
Churchill, E. N. and L. I. Szweda (2005). "Translocation of deltaPKC to mitochondria during cardiac reperfusion enhances superoxide anion production and induces loss in mitochondrial function." Arch Biochem Biophys 439(2): 194-199. (http://www.ncbi.nlm.nih.gov/pubmed/15963450)
Duilio, C., G. Ambrosio, P. Kuppusamy, A. DiPaula, L. C. Becker and J. L. Zweier (2001). "Neutrophils are primary source of O2 radicals during reperfusion after prolonged myocardial ischemia." Am J Physiol Heart Circ Physiol 280(6): H2649-2657. (http://www.ncbi.nlm.nih.gov/pubmed/11356621)
Hausenloy, D. J. and D. M. Yellon (2009). "Preconditioning and postconditioning: underlying mechanisms and clinical application." Atherosclerosis 204(2): 334-341. (http://www.ncbi.nlm.nih.gov/pubmed/19081095)
Inagaki, K., H. S. Hahn, G. W. Dorn, 2nd and D. Mochly-Rosen (2003). "Additive protection of the ischemic heart ex vivo by combined treatment with delta-protein kinase C inhibitor and epsilon-protein kinase C activator." Circulation 108(7): 869-875. (http://www.ncbi.nlm.nih.gov/pubmed/12860903)
Inagaki, K., Y. Kihara, W. Hayashida, T. Izumi, Y. Iwanaga, T. Yoneda, Y. Takeuchi, K. Suyama, E. Muso and S. Sasayama (2000). "Anti-ischemic effect of a novel cardioprotective agent, JTV519, is mediated through specific activation of delta-isoform of protein kinase C in rat ventricular myocardium." Circulation 101(7): 797-804. (http://www.ncbi.nlm.nih.gov/pubmed/10683355)
Kilpatrick, L. E., Y. H. Song, M. W. Rossi and H. M. Korchak (2000). "Serine phosphorylation of p60 tumor necrosis factor receptor by PKC-delta in TNF-alpha-activated neutrophils." Am J Physiol Cell Physiol 279(6): C2011-2018. (http://www.ncbi.nlm.nih.gov/pubmed/11078718)
Korchak, H. M., M. W. Rossi and L. E. Kilpatrick (1998). "Selective role for beta-protein kinase C in signaling for O-2 generation but not degranulation or adherence in differentiated HL60 cells." J Biol Chem 273(42): 27292-27299. (http://www.ncbi.nlm.nih.gov/pubmed/9765254)
Kwak, H. J., K. M. Park, H. E. Choi, H. J. Lim, J. H. Park and H. Y. Park (2010). "The cardioprotective effects of zileuton, a 5-lipoxygenase inhibitor, are mediated by COX-2 via activation of PKC delta." Cell Signal 22(1): 80-87. (http://www.ncbi.nlm.nih.gov/pubmed/19781629)
Laudanna, C., D. Mochly-Rosen, T. Liron, G. Constantin and E. C. Butcher (1998). "Evidence of zeta protein kinase C involvement in polymorphonuclear neutrophil integrin-dependent adhesion and chemotaxis." J Biol Chem 273(46): 30306-30315. (http://www.ncbi.nlm.nih.gov/pubmed/9804792)
Lefer, A. M. and D. J. Lefer (1996). "The role of nitric oxide and cell adhesion molecules on the microcirculation in ischaemia-reperfusion." Cardiovasc Res 32(4): 743-751. (http://www.ncbi.nlm.nih.gov/pubmed/8915192)
Liao, Y. F., Y. C. Hung, W. H. Chang, G. J. Tsay, T. C. Hour, H. C. Hung and G. Y. Liu (2005). "The PKC delta inhibitor, rottlerin, induces apoptosis of haematopoietic cell lines through mitochondrial membrane depolarization and caspases' cascade." Life Sci 77(6): 707-719. (http://www.ncbi.nlm.nih.gov/pubmed/15922001)
Lucchesi, B. R., S. W. Werns and J. C. Fantone (1989). "The role of the neutrophil and free radicals in ischemic myocardial injury." J Mol Cell Cardiol 21(12): 1241-1251. (http://www.ncbi.nlm.nih.gov/pubmed/2698962)
Majumdar, S., M. W. Rossi, T. Fujiki, W. A. Phillips, S. Disa, C. F. Queen, R. B. Johnston, Jr., O. M. Rosen, B. E. Corkey and H. M. Korchak (1991). "Protein kinase C isotypes and signaling in neutrophils. Differential substrate specificities of a translocatable calcium- and phospholipid-dependent beta-protein kinase C and a phospholipid-dependent protein kinase which is inhibited by long chain fatty acyl coenzyme A." J Biol Chem 266(14): 9285-9294. (http://www.ncbi.nlm.nih.gov/pubmed/2026625)
Mao, J. T., I. H. Tsu, S. M. Dubinett, B. Adams, T. Sarafian, F. Baratelli, M. D. Roth and K. J. Serio (2004). "Modulation of pulmonary leukotriene B4 production by cyclooxygenase-2 inhibitors and lipopolysaccharide." Clin Cancer Res 10(20): 6872-6878. (http://www.ncbi.nlm.nih.gov/pubmed/15501964)
Mayr, M., Y. L. Chung, U. Mayr, E. McGregor, H. Troy, G. Baier, M. Leitges, M. J. Dunn, J. R. Griffiths and Q. Xu (2004). "Loss of PKC-delta alters cardiac metabolism." Am J Physiol Heart Circ Physiol 287(2): H937-945. (http://www.ncbi.nlm.nih.gov/pubmed/15277208)
Mayr, M., B. Metzler, Y. L. Chung, E. McGregor, U. Mayr, H. Troy, Y. Hu, M. Leitges, O. Pachinger, J. R. Griffiths, M. J. Dunn and Q. Xu (2004). "Ischemic preconditioning exaggerates cardiac damage in PKC-delta null mice." Am J Physiol Heart Circ Physiol 287(2): H946-956. (http://www.ncbi.nlm.nih.gov/pubmed/15277209)
Mitchell, M. B., X. Meng, L. Ao, J. M. Brown, A. H. Harken and A. Banerjee (1995). "Preconditioning of isolated rat heart is mediated by protein kinase C." Circ Res 76(1): 73-81. (http://www.ncbi.nlm.nih.gov/pubmed/8001280)
Nishizuka, Y. (1992). "Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C." Science 258(5082): 607-614. (http://www.ncbi.nlm.nih.gov/pubmed/1411571)
Omiyi, D., R. J. Brue, P. Taormina, 2nd, M. Harvey, N. Atkinson and L. H. Young (2005). "Protein kinase C betaII peptide inhibitor exerts cardioprotective effects in rat cardiac ischemia/reperfusion injury." J Pharmacol Exp Ther 314(2): 542-551. (http://www.ncbi.nlm.nih.gov/pubmed/15878997)
Perkins, K. A., S. Pershad, Q. Chen, S. McGraw, J. S. Adams, C. Zambrano, S. Krass, J. Emrich, B. Bell, M. Iyamu, C. Prince, H. Kay, J. C. Teng and L. H. Young (2012). "The effects of modulating eNOS activity and coupling in ischemia/reperfusion (I/R)." Naunyn Schmiedebergs Arch Pharmacol 385(1): 27-38. (http://www.ncbi.nlm.nih.gov/pubmed/21947254)
Peterman, E. E., P. Taormina, 2nd, M. Harvey and L. H. Young (2004). "Go 6983 exerts cardioprotective effects in myocardial ischemia/reperfusion." J Cardiovasc Pharmacol 43(5): 645-656. (http://www.ncbi.nlm.nih.gov/pubmed/15071351)
Phillipson, A., E. E. Peterman, P. Taormina, Jr., M. Harvey, R. J. Brue, N. Atkinson, D. Omiyi, U. Chukwu and L. H. Young (2005). "Protein kinase C-zeta inhibition exerts cardioprotective effects in ischemia-reperfusion injury." Am J Physiol Heart Circ Physiol 289(2): H898-907. (http://www.ncbi.nlm.nih.gov/pubmed/15792991)
Pomerantz, B. J., T. N. Robinson, J. K. Heimbach, C. M. Calkins, S. A. Miller, A. Banerjee and A. H. Harken (2000). "Selective mitochondrial KATP channel opening controls human myocardial preconditioning: too much of a good thing?" Surgery 128(2): 368-373. (http://www.ncbi.nlm.nih.gov/pubmed/10923018)
Shandelya, S. M., P. Kuppusamy, M. L. Weisfeldt and J. L. Zweier (1993). "Evaluation of the role of polymorphonuclear leukocytes on contractile function in myocardial reperfusion injury. Evidence for plasma-mediated leukocyte activation." Circulation 87(2): 536-546. (http://www.ncbi.nlm.nih.gov/pubmed/8381059)
Strasser, R. H., R. Braun-Dullaeus, H. Walendzik and R. Marquetant (1992). "Alpha 1-receptor-independent activation of protein kinase C in acute myocardial ischemia. Mechanisms for sensitization of the adenylyl cyclase system." Circ Res 70(6): 1304-1312. (http://www.ncbi.nlm.nih.gov/pubmed/1315640)
Teng, J. C., H. Kay, Q. Chen, J. S. Adams, C. Grilli, G. Guglielmello, C. Zambrano, S. Krass, A. Bell and L. H. Young (2008). "Mechanisms related to the cardioprotective effects of protein kinase C epsilon (PKC epsilon) peptide activator or inhibitor in rat ischemia/reperfusion injury." Naunyn Schmiedebergs Arch Pharmacol 378(1): 1-15. (http://www.ncbi.nlm.nih.gov/pubmed/18496674)
Tsao, P. S. and A. M. Lefer (1990). "Time course and mechanism of endothelial dysfunction in isolated ischemic- and hypoxic-perfused rat hearts." Am J Physiol 259(6 Pt 2): H1660-1666. (http://www.ncbi.nlm.nih.gov/pubmed/2260693)
Vinten-Johansen, J. (2004). "Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury." Cardiovasc Res 61(3): 481-497. (http://www.ncbi.nlm.nih.gov/pubmed/14962479)
Wang, Y., K. Hirai and M. Ashraf (1999). "Activation of mitochondrial ATP-sensitive K(+) channel for cardiac protection against ischemic injury is dependent on protein kinase C activity." Circ Res 85(8): 731-741. (http://www.ncbi.nlm.nih.gov/pubmed/10521247)
Yellon, D. M. and D. J. Hausenloy (2007). "Myocardial reperfusion injury." N Engl J Med 357(11): 1121-1135. (http://www.ncbi.nlm.nih.gov/pubmed/17855673)
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