Defective metabolic signaling in adenylate kinase AK1 gene knock-out hearts compromises post-ischemic coronary reflow.
Matching blood flow to myocardial energy demand is vital for heart performance and recovery following ischemia. The molecular mechanisms responsible for transduction of myocardial energetic signals into reactive vasodilatation are, however, elusive. Adenylate kinase, associated with AMP signaling, is a sensitive reporter of the cellular energy state, yet the contribution of this phosphotransfer system in coupling myocardial metabolism with coronary flow has not been explored. Here, knock out of the major adenylate kinase isoform, AK1, disrupted the synchrony between inorganic phosphate P(i) turnover at ATP-consuming sites and gamma-ATP exchange at ATP synthesis sites, as revealed by (18)O-assisted (31)P NMR. This reduced energetic signal communication in the post-ischemic heart. AK1 gene deletion blunted vascular adenylate kinase phosphotransfer, compromised the contractility-coronary flow relationship, and precipitated inadequate coronary reflow following ischemia-reperfusion. Deficit in adenylate kinase activity abrogated AMP signal generation and reduced the vascular adenylate kinase/creatine kinase activity ratio essential for the response of metabolic sensors. The sarcolemma-associated splice variant AK1beta facilitated adenosine production, a function lost in the absence of adenylate kinase activity. Adenosine treatment bypassed AK1 deficiency and restored post-ischemic flow to wild-type levels, achieving phenotype rescue. AK1 phosphotransfer thus transduces stress signals into adequate vascular response, providing linkage between cell bioenergetics and coronary flow.
Dzeja
Petras P
PP
Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics, Mayo Clinic, Rochester, Minnesota 55905, USA. dzeja.petras@mayo.edu
Bast
Peter
P
Pucar
Darko
D
Wieringa
Be
B
Terzic
Andre
A
D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D003402:Creatine Kinase / Q000378:metabolism; D004734:Energy Metabolism; D017353:Gene Deletion; D006321:Heart / Q000503:physiopathology; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000503:physiopathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010103:Oxygen Isotopes / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010759:Phosphorus Isotopes / Q000378:metabolism; D015398:Signal Transduction
D007527:Isoenzymes; D010103:Oxygen Isotopes; D010750:Phosphoproteins; D010759:Phosphorus Isotopes; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D003402:Creatine Kinase; D000263:Adenylate Kinase; C110939:adenylate kinase 1
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