Details

Autor(en) / Beteiligte

• Lankford, Amy R
• Yang, Jiang-Ning
• Rose'Meyer, Roselyn
• French, Brent A
• Matherne, G. Paul
• Fredholm, Bertil B
• Yang, Zequan

Titel

Effect of modulating cardiac A1 adenosine receptor expression on protection with ischemic preconditioning

Ist Teil von

• American journal of physiology. Heart and circulatory physiology, 2006-04, Vol.290 (4), p.H1469-H1473

Ort / Verlag

United States

Erscheinungsjahr

2006

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 1 Department of Pediatrics, 2 Cardiovascular Research Center, and 3 Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia; 4 Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden; and 5 Griffith University, Gold Coast, Queensland, Australia Submitted 22 February 2005 ; accepted in final form 10 November 2005 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. myocardial ischemia-reperfusion injury; functional genomics; genetically altered mice Address for reprint requests and other correspondence: A. R. Lankford, Dept. of Pediatrics, Univ. of Virginia Health System Box 800386, MR4 Bldg., Charlottesville, VA 22908 (e-mail: arl2b{at}virginia.edu )