Adenylate kinase AK1 knockout heart: Energetics and functional performance under ischemia-reperfusion

Darko Pucar, Peter Bast, Richard J. Gumina, Lynette Lim, Carmen Drahl, Nenad Juranic, Slobodan Macura, Edwin Janssen, Be Wieringa, Andre Terzic, Petras P. Dzeja

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Deletion of the major adenylate kinase AK1 isoform, which catalyzes adenine nucleotide exchange, disrupts cellular energetic economy and compromises metabolic signal transduction. However, the consequences of deleting the AK1 gene on cardiac energetic dynamics and performance in the setting of ischemia-reperfusion have not been determined. Here, at the onset of ischemia, AK1 knockout mice hearts displayed accelerated loss of contractile force compared with 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-to-Pi and creatine phosphate-to-Pi ratios. Postischemic AK1 knockout hearts maintained ∼ 40% of β-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-to-ADP ratio and total ATP turnover rate, maintained postischemic contractile recovery of AK1 knockout hearts at wild-type levels. Thus deletion of the AK1 gene reveals that adenylate kinase phosphotransfer supports myocardial function on initiation of ischemic stress and safeguards intracellular nucleotide pools in postischemic recovery.

Original languageEnglish (US)
Pages (from-to)H776-H782
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume283
Issue number2 52-2
StatePublished - Jul 30 2002

Keywords

  • Adenine nucleotides
  • Energy metabolism
  • Glycolysis
  • Oxygen-18 phosphoryl labeling
  • Phosphorus-31 nuclear magnetic resonance
  • Phosphotransfer

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Pucar, D., Bast, P., Gumina, R. J., Lim, L., Drahl, C., Juranic, N., Macura, S., Janssen, E., Wieringa, B., Terzic, A., & Dzeja, P. P. (2002). Adenylate kinase AK1 knockout heart: Energetics and functional performance under ischemia-reperfusion. American Journal of Physiology - Heart and Circulatory Physiology, 283(2 52-2), H776-H782.