This is a revised grant application from a new investigator. The goal of this proposal is to study the mechanisms by which A3 adenosine receptors (A3AR) are cardioprotective for ischemia, and to study the effect of cardiac-specific overexpression of A3 adenosine receptors on resistance to ischemic injury and development of adenosine tolerance. The hypothesis is that A3 adenosine receptors provide cardioprotection via ATP-dependent potassium channels (KATP), involving the sequential activation of Gi/o proteins, PKC, and MAPK pathways. Using A3 adenosine receptor stimulated adult rabbit myocytes, measurements will be made of PKC isoforms, and activation of P44, P42, P38, and JNK will be examined. Specific PKC isoforms and MAPK pathways will be blocked, and the effect on cardioprotection will be assessed in vitro with ischemic myocytes, and in vivo with infarcted rabbit hearts. These same models will be used with pertussis toxin or with specific KATP channel inhibitors to study the role of Gi/o proteins and KATP channels. The second hypothesis is that cardiac A3 adenosine receptor overexpression in transgenic mice will protect from ischemia and prevent adenosine tolerance. Initially, cardiac function will be studied via physiology, biochemistry, and pathology studies. Then resistance to ischemic injury and to adenosine tolerance will be evaluated in a murine infarction model and an isolated heart model of global ischemia. The results will provide understanding of the mechanisms of A3 adenosine receptor cardioprotection, and may allow for development of molecular strategies to treat ischemic heart disease with increased expression of A3 adenosine receptors.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060051-05
Application #
6476835
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Balshaw, David M
Project Start
1998-12-15
Project End
2003-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
5
Fiscal Year
2002
Total Cost
$139,295
Indirect Cost
Name
Medical College of Wisconsin
Department
Pharmacology
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Xiang, Sunny Yang; Ye, Linda L; Duan, Li-lu Marie et al. (2011) Characterization of a critical role for CFTR chloride channels in cardioprotection against ischemia/reperfusion injury. Acta Pharmacol Sin 32:824-33
Auchampach, John A; Kreckler, Laura M; Wan, Tina C et al. (2009) Characterization of the A2B adenosine receptor from mouse, rabbit, and dog. J Pharmacol Exp Ther 329:2-13
Kreckler, Laura M; Gizewski, Elizabeth; Wan, Tina C et al. (2009) Adenosine suppresses lipopolysaccharide-induced tumor necrosis factor-alpha production by murine macrophages through a protein kinase A- and exchange protein activated by cAMP-independent signaling pathway. J Pharmacol Exp Ther 331:1051-61
van der Hoeven, Dharini; Wan, Tina C; Auchampach, John A (2008) Activation of the A(3) adenosine receptor suppresses superoxide production and chemotaxis of mouse bone marrow neutrophils. Mol Pharmacol 74:685-96
Wan, Tina C; Ge, Zhi-Dong; Tampo, Akihito et al. (2008) The A3 adenosine receptor agonist CP-532,903 [N6-(2,5-dichlorobenzyl)-3'-aminoadenosine-5'-N-methylcarboxamide] protects against myocardial ischemia/reperfusion injury via the sarcolemmal ATP-sensitive potassium channel. J Pharmacol Exp Ther 324:234-43
Gross, Garrett J; Auchampach, John A (2007) Reperfusion injury: does it exist? J Mol Cell Cardiol 42:12-8
Auchampach, John A (2007) Adenosine receptors and angiogenesis. Circ Res 101:1075-7
Kreckler, Laura M; Wan, Tina C; Ge, Zhi-Dong et al. (2006) Adenosine inhibits tumor necrosis factor-alpha release from mouse peritoneal macrophages via A2A and A2B but not the A3 adenosine receptor. J Pharmacol Exp Ther 317:172-80
Ge, Zhi-Dong; Peart, Jason N; Kreckler, Laura M et al. (2006) Cl-IB-MECA [2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide] reduces ischemia/reperfusion injury in mice by activating the A3 adenosine receptor. J Pharmacol Exp Ther 319:1200-10
Auchampach, John A; Jin, Xiaowei; Moore, Jeannine et al. (2004) Comparison of three different A1 adenosine receptor antagonists on infarct size and multiple cycle ischemic preconditioning in anesthetized dogs. J Pharmacol Exp Ther 308:846-56

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