Abstract

The goal of this research is to define the mechanisms by which A3 adenosine receptors (ARs) protect against myocardial ischemia/reperfusion injury. We will test the hypothesis that A3ARs are protective by multiple mechanisms including preservation of mitochondrial function, reduction of apoptosis, and attenuation of inflammation. We predict that the A3AR signals via kinase signaling pathways that ultimately results in protection by activation of mitochondrial KATP channels. A key feature of our hypothesis is that we predict that A3ARs are expressed in cardiac myocytes. We will test these hypotheses by examining the effect of selective A3AR agonists in an isolated mouse heart model of global ischemia/reperfusion and a clinically relevant in vivo dog model of infarction. The isolated mouse heart model will be used to correlate post-ischemic contractile function (left ventricular pressure) and cell necrosis (LDH released) with metabolic state (high-energy phosphates), mitochondrial integrity (mitochondrial membrane potential, respiration, and rate of ATP synthesis), apoptosis (DNA fragmentation, TUNEL staining, caspase activation), and pro-inflammatory cytokine signaling (NF kappa B activation, TNF alpha production). The in vivo dog model of infarction will be used to compare infarct size with markers of inflammation (neutrophil infiltration). The mitochondrial specific KATP channel blocker sodium 5-hydroxydecanoate will be used to delineate the role of mitochondrial KATP channels in preserving mitochondrial and cardiac function. Experiments will be performed to determine whether A3ARs signal via specific protein kinases (PKC-epsilon or delta; PI-3/akt kinase) and/or generation of reactive oxygen species. Information obtained from these studies will advance the understanding of the fundamental questions involved in cellular protection. The results of theses studies should also provide new insights into the therapeutic utility of targeting A3ARs in patients with ischemic heart disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060051-10
Application #
7195826
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Schwartz, Lisa
Project Start
1998-12-15
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
10
Fiscal Year
2007
Total Cost
$115,618
Indirect Cost

  Institution

Name
Medical College of Wisconsin
Department
Pharmacology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226

  Publications

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

Showing the most recent 10 out of 15 publications