Abstract

This proposal will test several new hypotheses concerning the mechanism of protection provided by preconditioning. Because of the proposed central importance of PKC to preconditioning's protection and the controversy surrounding its involvement in larger species such as the dog and pig, the requirement of PKC activation in preconditioning in isolated canine cardiomyocytes will be determined to evaluate whether technical factors or true species differences have heretofore prevented confirmation of the PKC hypothesis in dogs. Recent data reveal that tyrosine kinase activation is also involved in the protection, and that is downstream of PKC, thus forming a kinase cascade. The investigators will test the involvement of several of the tyrosine kinase cascades, especially the p38 MAPK pathway, in ischemic and pharmacologic preconditioning. They will further test the hypothesis that this pathway to protection terminates in inhibition of a protein phosphatase with ultimate preservation of constitutively phosphorylated proteins, possibly cytoskeletal elements.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050688-06
Application #
6056263
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1993-09-01
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of South Alabama
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Mobile
State
AL
Country
United States
Zip Code
36688

  Publications

Tissier, Renaud; Chenoune, Mourad; Ghaleh, Bijan et al. (2010) The small chill: mild hypothermia for cardioprotection? Cardiovasc Res 88:406-14
Kuno, Atsushi; Solenkova, Nataliya V; Solodushko, Victoriya et al. (2008) Infarct limitation by a protein kinase G activator at reperfusion in rabbit hearts is dependent on sensitizing the heart to A2b agonists by protein kinase C. Am J Physiol Heart Circ Physiol 295:H1288-H1295
Liu, Yanping; Yang, Xi-Ming; Iliodromitis, Efstathios K et al. (2008) Redox signaling at reperfusion is required for protection from ischemic preconditioning but not from a direct PKC activator. Basic Res Cardiol 103:54-9
Costa, Alexandre D T; Pierre, Sandrine V; Cohen, Michael V et al. (2008) cGMP signalling in pre- and post-conditioning: the role of mitochondria. Cardiovasc Res 77:344-52
Tissier, Renaud; Berdeaux, Alain; Ghaleh, Bijan et al. (2008) Making the heart resistant to infarction: how can we further decrease infarct size? Front Biosci 13:284-301
Tissier, R; Cohen, M V; Downey, J M (2007) Protecting the acutely ischemic myocardium beyond reperfusion therapies: are we any closer to realizing the dream of infarct size elimination? Arch Mal Coeur Vaiss 100:794-802
Kuno, Atsushi; Critz, Stuart D; Cui, Lin et al. (2007) Protein kinase C protects preconditioned rabbit hearts by increasing sensitivity of adenosine A2b-dependent signaling during early reperfusion. J Mol Cell Cardiol 43:262-71
Cohen, Michael V; Philipp, Sebastian; Krieg, Thomas et al. (2007) Preconditioning-mimetics bradykinin and DADLE activate PI3-kinase through divergent pathways. J Mol Cell Cardiol 42:842-51
Kuno, Atsushi; Critz, Stuart D; Cohen, Michael V et al. (2007) Nicorandil opens mitochondrial K(ATP) channels not only directly but also through a NO-PKG-dependent pathway. Basic Res Cardiol 102:73-9
Cohen, Michael V; Yang, Xi-Ming; Downey, James M (2007) The pH hypothesis of postconditioning: staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation 115:1895-903

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