The objectives are to determine the mechanisms by which preconditioning protect from ischemic injury. Preconditioning refers to a period of resistance to ischemic injury, that can be induced by temporary ischemic, hypoxia or adenosine A1 receptors, prior to a period of sustained ischemic. Neither at the natural trigger, the target tissue (nerve, vascular, myocyte or interstitial), nor the mechanisms responsible for in situ preconditioning have been established. To date, preconditioning has only been shown to occur in intact hearts or animals. A new observation is that isolated adult rabbit cardiomyocytes can be endogenously preconditioned against subsequent ischemia, by a brief, substrate-free, oxygenated incubation period. This preconditioning conferes a high degree of protection (1-2 hour delay in death) from subsequent ischemia. In vitro- preconditioning mechanisms do not appear related to energy utilization/production, or to catacholamines. This proposal, focuses on characterization of this new model, as a basis for future studies of endogenous cellular mechanisms of preconditioning.
The aims are to determine; A. the relations between protection and high energy phosphate levels; B. if the trigger, and protection are/are not analogous to that in intact hearts; C. if preconditioning decays during a post incubation period prior to ischemia; D. determine if the pathways of preconditioning, and protein phosphatase inhibitors converge to a common PKC-related pathway; E. determine if preconditioning can be induced in vitro, in another species. This new in vitro model will be useful in determination of mechanisms of endogenous cellular myocardial protection, which could allow development of a new class of therapeutic agents to reduce infarct size, or lead to better methods of organ preservation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL051859-01
Application #
2228852
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1994-08-01
Project End
1997-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
East Tennessee State University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Johnson City
State
TN
Country
United States
Zip Code
37614
Armstrong, Stephen C; Latham, Carole A; Ganote, Charles E (2003) An ischemic beta-dystroglycan (betaDG) degradation product: correlation with irreversible injury in adult rabbit cardiomyocytes. Mol Cell Biochem 242:71-9
Diaz, Roberto J; Armstrong, Stephen C; Batthish, Michelle et al. (2003) Enhanced cell volume regulation: a key protective mechanism of ischemic preconditioning in rabbit ventricular myocytes. J Mol Cell Cardiol 35:45-58
Ganote, Charles E; Armstrong, Stephen C (2003) Effects of CCCP-induced mitochondrial uncoupling and cyclosporin A on cell volume, cell injury and preconditioning protection of isolated rabbit cardiomyocytes. J Mol Cell Cardiol 35:749-59
Armstrong, S C; Shivell, L C; Ganote, C E (2001) Sarcolemmal blebs and osmotic fragility as correlates of irreversible ischemic injury in preconditioned isolated rabbit cardiomyocytes. J Mol Cell Cardiol 33:149-60
Armstrong, S C; Latham, C A; Shivell, C L et al. (2001) Ischemic loss of sarcolemmal dystrophin and spectrin: correlation with myocardial injury. J Mol Cell Cardiol 33:1165-79
Armstrong, S C; Shivell, C L; Ganote, C E (2000) Differential translocation or phosphorylation of alpha B crystallin cannot be detected in ischemically preconditioned rabbit cardiomyocytes. J Mol Cell Cardiol 32:1301-14
Armstrong, S C; Gao, W; Lane, J R et al. (1998) Protein phosphatase inhibitors calyculin A and fostriecin protect rabbit cardiomyocytes in late ischemia. J Mol Cell Cardiol 30:61-73
Armstrong, S C; Kao, R; Gao, W et al. (1997) Comparison of in vitro preconditioning responses of isolated pig and rabbit cardiomyocytes: effects of a protein phosphatase inhibitor, fostriecin. J Mol Cell Cardiol 29:3009-24
Armstrong, S C; Hoover, D B; Shivell, L C et al. (1997) Preconditioning of isolated rabbit cardiomyocytes: no evident separation of induction, memory and protection. J Mol Cell Cardiol 29:2285-98
Rice, P J; Armstrong, S C; Ganote, C E (1996) Concentration-response relationships for adenosine agonists during preconditioning of rabbit cardiomyocytes. J Mol Cell Cardiol 28:1355-65

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