Myocardial damage from ischemia with coronary vascular disease causes significant morbidity and mortality. The investigators have been studying the effects of endogenous protective mechanisms, such as adenosine, to provide tolerance to ischemia. The investigators note that acting at A1 receptors, adenosine reduces ischemia-reperfusion injury and mediates ischemic preconditioning. In addition they state that the heart must also adapt to changing metabolic needs to avoid injury from imbalances in myocardial oxygen supply and demand. When the metabolic demands of the heart are greater than the oxygen supply (demand ischemia), the investigators indicate that adenosine acts via the A1 adenosine receptor to directly protect the myocardium. Thus, the investigators conclude that activation of A1 receptors can provide protection to the heart during bot ischemia and """"""""demand ischemia"""""""". This proposal adopts the approach of overexpressing myocardial A1 adenosine receptors with transgenic techniques to enhance the intrinsic tolerance of the myocardium to ischemia reperfusion, and demand ischemia. The central hypothesis of this proposal is that a transgenic model of increased cardiac A1 receptors will have increased protection from ischemia- reperfusion and from decreases in the oxygen supply to demand ratio (""""""""demand ischemia""""""""). The long range goal is an integrated analysis of the role of A1 receptors in cardioprotection in order to identify the mechanism of this protection. The investigators will evaluate the functional, bioenergetic, biochemical, and ultrastructural response to ischemia in transgenic mice and will assess the mechanism(s) of A1 adenosine receptor-mediated myocardial protection by identifying the signaling pathways involved and evaluating the cellular mechanisms by assessing calcium transport and glucose metabolism.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059419-03
Application #
6183840
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1998-07-10
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
3
Fiscal Year
2000
Total Cost
$274,116
Indirect Cost
Name
University of Virginia
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Lankford, Amy R; Yang, Jiang-Ning; Rose'Meyer, Roselyn et al. (2006) Effect of modulating cardiac A1 adenosine receptor expression on protection with ischemic preconditioning. Am J Physiol Heart Circ Physiol 290:H1469-73
Willems, Laura; Headrick, John P (2005) Protecting murine hearts from ischaemia-reperfusion using selective inhibitors of adenosine metabolism. Clin Exp Pharmacol Physiol 32:179-83
Neumann, Joachim; Boknik, Peter; Matherne, G Paul et al. (2003) Pertussis toxin sensitive and insensitive effects of adenosine and carbachol in murine atria overexpressing A(1)-adenosine receptors. Br J Pharmacol 138:209-17
Regan, Sara E; Broad, Michael; Byford, Anne M et al. (2003) A1 adenosine receptor overexpression attenuates ischemia-reperfusion-induced apoptosis and caspase 3 activity. Am J Physiol Heart Circ Physiol 284:H859-66
Ashton, Kevin J; Holmgren, Kirsty; Peart, Jason et al. (2003) Effects of A1 adenosine receptor overexpression on normoxic and post-ischemic gene expression. Cardiovasc Res 57:715-26
Neumann, Joachim; Boknik, Peter; Begrow, Frank et al. (2003) Altered signal transduction in cardiac ventricle overexpressing A(1)-adenosine receptors. Cardiovasc Res 60:529-37
Harrison, Glenn J; Cerniway, Rachael J; Peart, Jason et al. (2002) Effects of A(3) adenosine receptor activation and gene knock-out in ischemic-reperfused mouse heart. Cardiovasc Res 53:147-55
Flood, Amanda J; Willems, Laura; Headrick, John P (2002) Coronary function and adenosine receptor-mediated responses in ischemic-reperfused mouse heart. Cardiovasc Res 55:161-70
Cerniway, Rachael J; Morrison, R Ray; Byford, Anne M et al. (2002) A1 adenosine receptor overexpression decreases stunning from anoxia-reoxygenation: role of the mitochondrial K(ATP) channel. Basic Res Cardiol 97:232-8
Yang, Zequan; Cerniway, Rachael J; Byford, Anne M et al. (2002) Cardiac overexpression of A1-adenosine receptor protects intact mice against myocardial infarction. Am J Physiol Heart Circ Physiol 282:H949-55

Showing the most recent 10 out of 18 publications