Document Detail


Creatine kinase overexpression improves ATP kinetics and contractile function in postischemic myocardium.
MedLine Citation:
PMID:  22886411     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Ashwin Akki; Jason Su; Toshiyuki Yano; Ashish Gupta; Yibin Wang; Michelle K Leppo; Vadappuram P Chacko; Charles Steenbergen; Robert G Weiss
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-10
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  303     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-02     Completed Date:  2012-12-14     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H844-52     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Acidosis / enzymology,  physiopathology
Adenosine Triphosphate / metabolism*
Animals
Creatine Kinase, MM Form / genetics,  metabolism*
Disease Models, Animal
Energy Metabolism* / genetics
Hydrogen-Ion Concentration
Kinetics
L-Lactate Dehydrogenase / metabolism
Magnetic Resonance Spectroscopy
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myocardial Contraction* / genetics
Myocardial Ischemia / enzymology*,  genetics,  physiopathology
Myocardial Reperfusion Injury / enzymology*,  genetics,  physiopathology
Myocardium / enzymology*
Phosphocreatine / metabolism
Up-Regulation
Grant Support
ID/Acronym/Agency:
HL-39752/HL/NHLBI NIH HHS; HL-63030/HL/NHLBI NIH HHS; R01 HL039752/HL/NHLBI NIH HHS; R01 HL098954/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
020IUV4N33/Phosphocreatine; 8L70Q75FXE/Adenosine Triphosphate; EC 1.1.1.27/L-Lactate Dehydrogenase; EC 2.7.3.2/Creatine Kinase, MM Form
Comments/Corrections

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