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Articles in PresS, published online ahead of print April 11, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00116.2002
Submitted on February 12, 2002
Accepted on April 3, 2002
1 Cardiovascular, Mayo Clinic, Rochester, MN, USA
2 Cell Biology, University of Nijmegen, Nijmegen, The Netherlands
* To whom correspondence should be addressed. E-mail: dzeja.petras{at}mayo.edu.
Deletion of the major adenylate kinase AK1 isoform, which catalyzes adenine nucleotide exchange, disrupts cellular energetic economy and compromises metabolic signal transduction. However, the consequence of deleting the AK1 gene on cardiac energetic dynamics and performance in the setting of ischemia-reperfusion has not been determined. Here, at the onset of ischemia, AK1-knockout mice hearts displayed accelerated loss of contractile force compared to wild-type controls, indicating reduced tolerance to ischemic stress. On reperfusion, AK1-knockout hearts demonstrated reduced nucleotide salvage, resulting in lower ATP, GTP, ADP and GDP levels, and an altered metabolic steady-state associated with diminished ATP/Pi and creatine phosphate/Pi ratios. Post-ischemic AK1-knockout hearts maintained ~40% of ß-phosphoryl turnover suggesting increased phosphotransfer flux through remaining adenylate kinase isoforms. This was associated with sustained creatine kinase flux and elevated cellular glucose-6-phosphate levels as the cellular energetic system adapted to deletion of AK1. Such metabolic rearrangements, along with sustained ATP/ADP ratio and total ATP turnover rate, maintained post-ischemic contractile recovery of AK1-knockout hearts at wild-type levels. Thus, deletion of the AK1 gene reveals that adenylate kinase phosphotransfer supports myocardial function upon initiation of ischemic stress, and safeguards intracellular nucleotide pools in post-ischemic recovery.
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