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Effect of modulating cardiac A1 adenosine receptor expression on protection with ischemic preconditioning
Amy R Lankford1, Jiang-Ning Yang, Roselyn Rose'Meyer
1Dept. of Pediatrics, University of Virginia Health System, Charlottesville, VA 22908, USA. arl2b@virginia.edu
Abstract:
Activation of A(1) adenosine receptors (A(1)ARs) may be a crucial step in protection against myocardial ischemia-reperfusion (I/R) injury; however, the use of pharmacological A(1)AR antagonists to inhibit myocardial protection has yielded inconclusive results. In the current study, we have used mice with genetically modified A(1)AR expression to define the role of A(1)AR in intrinsic protection and ischemic preconditioning (IPC) against I/R injury. Normal wild-type (WT) mice, knockout mice with deleted (A(1)KO(-/-)) or single-copy (A(1)KO(+/-)) A(1)AR, and transgenic mice (A(1)TG) with increased cardiac A(1)AR expression underwent 45 min of left anterior descending coronary artery occlusion, followed by 60 min of reperfusion. Subsets of each group were preconditioned with short durations of ischemia (3 cycles of 5 min of occlusion and 5 min of reperfusion) before index ischemia. Infarct size (IF) in WT, A(1)KO(+/-), and A(1)KO(-/-) mice was (in % of risk region) 58 +/- 3, 60 +/- 4, and 61 +/- 2, respectively, and was less in A(1)TG mice (39 +/- 4, P < 0.05). A strong correlation was observed between A(1)AR expression level and response to IPC. IF was significantly reduced by IPC in WT mice (35 +/- 3, P < 0.05 vs. WT), A(1)KO(+/-) + IPC (48 +/- 4, P < 0.05 vs. A(1)KO(+/-)), and A(1)TG + IPC mice (24 +/- 2, P < 0.05 vs. A(1)TG). However, IPC did not decrease IF in A(1)KO(-/-) + IPC mice (63 +/- 2). In addition, A(1)KO(-/-) hearts subjected to global I/R injury demonstrated diminished recovery of developed pressure and diastolic function compared with WT controls. These findings demonstrate that A(1)ARs are critical for protection from myocardial I/R injury and that cardioprotection with IPC is relative to the level of A(1)AR gene expression.
Insights
Activation of A(1) adenosine receptors (A(1)ARs) is crucial for protecting the heart against ischemia-reperfusion (I/R) injury. Cardioprotection from ischemic preconditioning (IPC) depends on the level of A(1)AR gene expression.
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- Myocardial ischemia-reperfusion (I/R) injury poses a significant clinical challenge.
- Activation of A(1) adenosine receptors (A(1)ARs) is implicated in endogenous cardioprotection.
- Pharmacological inhibition of A(1)ARs has yielded inconclusive results regarding their role in myocardial protection.
Purpose of the Study:
- To elucidate the role of A(1)ARs in intrinsic cardioprotection and ischemic preconditioning (IPC) against I/R injury.
- To investigate the correlation between A(1)AR expression levels and the response to IPC.
- To assess the functional recovery of the heart following I/R injury in mice with varying A(1)AR expression.
Main Methods:
- Utilized genetically modified mice: wild-type (WT), A(1)AR knockout (A(1)KO(-/-) and A(1)KO(+/-)), and transgenic (A(1)TG) with altered A(1)AR expression.
- Subjected mice to 45 minutes of coronary artery occlusion followed by 60 minutes of reperfusion (I/R injury).
- Applied ischemic preconditioning (IPC) protocol (3 cycles of 5 min occlusion/5 min reperfusion) to subsets of mice before I/R injury.
Main Results:
- Transgenic mice (A(1)TG) exhibited significantly reduced infarct size (IF) compared to WT mice (39% vs. 58%).
- IPC significantly reduced IF in WT, A(1)KO(+/-), and A(1)TG mice, but not in A(1)KO(-/-) mice.
- A strong positive correlation was observed between A(1)AR expression levels and the protective effect of IPC.
- A(1)KO(-/-) hearts showed impaired functional recovery (developed pressure, diastolic function) after global I/R injury compared to WT controls.
Conclusions:
- A(1)ARs are critical mediators of protection against myocardial I/R injury.
- The efficacy of IPC in providing cardioprotection is directly dependent on the level of A(1)AR gene expression.
- Genetic manipulation of A(1)AR levels significantly impacts myocardial response to I/R injury and IPC effectiveness.
