title: Creatine kinase overexpression improves ATP kinetics and contractile function in postischemic myocardium.
abstract: Reduced myofibrillar ATP availability during prolonged myocardial ischemia may limit post-ischemic mechanical function. Because creatine kinase (CK) is the prime energy reserve reaction of the heart and because it has been difficult to augment ATP synthesis during and after ischemia, we used mice that overexpress the myofibrillar isoform of creatine kinase (CKM) in cardiac-specific, conditional fashion to test the hypothesis that CKM overexpression increases ATP delivery in ischemic-reperfused hearts and improves functional recovery. Isolated, retrograde-perfused hearts from control and CKM mice were subjected to 25 min of global, no-flow ischemia and 40 min of reperfusion while cardiac function [rate pressure product (RPP)] was monitored. A combination of (31)P-nuclear magnetic resonance experiments at 11.7T and biochemical assays was used to measure the myocardial rate of ATP synthesis via CK (CK flux) and intracellular pH (pH(i)). Baseline CK flux was severalfold higher in CKM hearts (8.1 ± 1.0 vs. 32.9 ± 3.8, mM/s, control vs. CKM; P < 0.001) with no differences in phosphocreatine concentration [PCr] and RPP. End-ischemic pH(i) was higher in CKM hearts than in control hearts (6.04 ± 0.12 vs. 6.37 ± 0.04, control vs. CKM; P < 0.05) with no differences in [PCr] and [ATP] between the two groups. Post-ischemic PCr (66.2 ± 1.3 vs. 99.1 ± 8.0, %preischemic levels; P < 0.01), CK flux (3.2 ± 0.4 vs. 14.0 ± 1.2 mM/s; P < 0.001) and functional recovery (13.7 ± 3.4 vs. 64.9 ± 13.2%preischemic RPP; P < 0.01) were significantly higher and lactate dehydrogenase release was lower in CKM than in control hearts. Thus augmenting cardiac CKM expression attenuates ischemic acidosis, reduces injury, and improves not only high-energy phosphate content and the rate of CK ATP synthesis in postischemic myocardium but also recovery of contractile function.
authors.affiliation: Cardiology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287-6568, USA.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Akki
authors.forename: Jason
authors.initials: J
authors.lastname: Su
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yano
authors.forename: Ashish
authors.initials: A
authors.lastname: Gupta
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Leppo
authors.forename: Vadappuram P
authors.initials: VP
authors.lastname: Chacko
authors.forename: Charles
authors.initials: C
authors.lastname: Steenbergen
authors.forename: Robert G
authors.initials: RG
authors.lastname: Weiss
mesh_terms: D000138:Acidosis / Q000201:enzymology / Q000503:physiopathology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D052283:Creatine Kinase, MM Form / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology*; D010725:Phosphocreatine / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D010725:Phosphocreatine; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D052283:Creatine Kinase, MM Form