© 2000 American Heart Association, Inc.
Cellular Biology |
Ischemic Preconditioning Activates Phosphatidylinositol-3-Kinase Upstream of Protein Kinase C
From the Laboratory of Molecular Carcinogenesis (H.T., E.M.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, and Department of Pathology (W.C., C.S.), Duke University Medical Center, Durham, NC.
Correspondence to Haiyan Tong, Mail drop D2-03, NIEHS, Research Triangle Park, NC 27709. E-mail tong{at}niehs.nih.gov
Abstract—The present study is
designed to test whether phosphatidylinositol 3-kinase (PI3-kinase) has
a role in the signaling pathway in ischemic preconditioning
(PC) and whether it is proximal or distal to protein kinase C (PKC).
Before 20 minutes of global ischemia, Langendorff-perfused rat
hearts were perfused for 20 minutes (control); preconditioned with 4
cycles of 5-minute ischemia and 5-minute reflow (PC); treated
with either wortmannin (WM) or LY 294002 (LY), each of which is a
PI3-kinase inhibitor, for 5 minutes before and throughout
PC; treated with 1,2-dioctanoyl-sn-glycerol (DOG), an
activator of PKC for 10 minutes (DOG); treated identically
to the DOG group except with WM added 10 minutes before and during
perfusion with DOG; or treated with either WM or LY for 25 minutes.
Recovery of left ventricular developed pressure (LVDP;
percentage of initial preischemic LVDP), measured after 30
minutes of reflow, was improved by PC (72±2% versus 36±4% in
control; P<0.001), and this was blocked by WM and LY
(41±4% and 43±5%, respectively; P<0.05 compared
with PC). DOG addition improved postischemic LVDP (67±6%;
P<0.001 compared with control), but in contrast to its
effect on PC, WM did not completely eliminate the protective effect of
DOG (52±4%; P>0.05 compared with DOG;
P<0.05 compared with control). PC induced
phosphorylation of protein kinase B and translocation
of PKC
, and it increased NO production, and these effects
were blocked by WM, which suggests a role for PI3-kinase in PC upstream
of PKC and NO.
Key Words: phosphatidylinositol 3-kinase • protein kinase C • nitric oxide • ischemic preconditioning
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H.-Z. Zhou, J. S. Karliner, and M. O. Gray Moderate alcohol consumption induces sustained cardiac protection by activating PKC-epsilon and Akt Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H165 - H174. [Abstract] [Full Text] [PDF]
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S. Uddin, A. Sassano, D. K. Deb, A. Verma, B. Majchrzak, A. Rahman, A. B. Malik, E. N. Fish, and L. C. Platanias Protein Kinase C-delta (PKC-delta ) Is Activated by Type I Interferons and Mediates Phosphorylation of Stat1 on Serine 727 J. Biol. Chem., April 19, 2002; 277(17): 14408 - 14416. [Abstract] [Full Text] [PDF]
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H. Tong, K. Imahashi, C. Steenbergen, and E. Murphy Phosphorylation of Glycogen Synthase Kinase-3{beta} During Preconditioning Through a Phosphatidylinositol-3-Kinase-Dependent Pathway Is Cardioprotective Circ. Res., March 8, 2002; 90(4): 377 - 379. [Abstract] [Full Text] [PDF]
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R. Schulz, M. V Cohen, M. Behrends, J. M Downey, and G. Heusch Signal transduction of ischemic preconditioning Cardiovasc Res, November 1, 2001; 52(2): 181 - 198. [Full Text] [PDF]
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R. M Bell and D. M Yellon The contribution of endothelial nitric oxide synthase to early ischaemic preconditioning: the lowering of the preconditioning threshold. An investigation in eNOS knockout mice Cardiovasc Res, November 1, 2001; 52(2): 274 - 280. [Abstract] [Full Text] [PDF]
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K. Mubagwa and W. Flameng Adenosine, adenosine receptors and myocardial protection: An updated overview Cardiovasc Res, October 1, 2001; 52(1): 25 - 39. [Abstract] [Full Text] [PDF]
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T. M. Vondriska, J. B. Klein, and P. Ping Use of functional proteomics to investigate PKC{epsilon}-mediated cardioprotection: the signaling module hypothesis Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1434 - H1441. [Abstract] [Full Text] [PDF]
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K. Yamashita, J. Kajstura, D. J. Discher, B. J. Wasserlauf, N. H. Bishopric, P. Anversa, and K. A. Webster Reperfusion-Activated Akt Kinase Prevents Apoptosis in Transgenic Mouse Hearts Overexpressing Insulin-Like Growth Factor-1 Circ. Res., March 30, 2001; 88(6): 609 - 614. [Abstract] [Full Text] [PDF]
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J. M. Pass, Y. Zheng, W. B. Wead, J. Zhang, R. C. X. Li, R. Bolli, and P. Ping PKC{epsilon} activation induces dichotomous cardiac phenotypes and modulates PKC{epsilon}-RACK interactions and RACK expression Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H946 - H955. [Abstract] [Full Text] [PDF]
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T. M. Vondriska, J. Zhang, C. Song, X.-L. Tang, X. Cao, C. P. Baines, J. M. Pass, S. Wang, R. Bolli, and P. Ping Protein Kinase C {epsilon}-Src Modules Direct Signal Transduction in Nitric Oxide-Induced Cardioprotection : Complex Formation as a Means for Cardioprotective Signaling Circ. Res., June 22, 2001; 88(12): 1306 - 1313. [Abstract] [Full Text] [PDF]
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J.L. Mehta, H.J. Chen, and D.Y. Li Protection of Myocytes From Hypoxia-Reoxygenation Injury by Nitric Oxide Is Mediated by Modulation of Transforming Growth Factor-{beta}1 Circulation, May 7, 2002; 105(18): 2206 - 2211. [Abstract] [Full Text] [PDF]
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