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Creatine kinase overexpression improves ATP kinetics and contractile function in postischemic myocardium.

Publication ,  Journal Article
Akki, A; Su, J; Yano, T; Gupta, A; Wang, Y; Leppo, MK; Chacko, VP; Steenbergen, C; Weiss, RG
Published in: Am J Physiol Heart Circ Physiol
October 1, 2012

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.

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Published In

Am J Physiol Heart Circ Physiol

DOI

EISSN

1522-1539

Publication Date

October 1, 2012

Volume

303

Issue

7

Start / End Page

H844 / H852

Location

United States

Related Subject Headings

  • Up-Regulation
  • Phosphocreatine
  • Myocardium
  • Myocardial Reperfusion Injury
  • Myocardial Ischemia
  • Myocardial Contraction
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Male
 

Citation

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Akki, A., Su, J., Yano, T., Gupta, A., Wang, Y., Leppo, M. K., … Weiss, R. G. (2012). Creatine kinase overexpression improves ATP kinetics and contractile function in postischemic myocardium. Am J Physiol Heart Circ Physiol, 303(7), H844–H852. https://doi.org/10.1152/ajpheart.00268.2012
Akki, Ashwin, Jason Su, Toshiyuki Yano, Ashish Gupta, Yibin Wang, Michelle K. Leppo, Vadappuram P. Chacko, Charles Steenbergen, and Robert G. Weiss. “Creatine kinase overexpression improves ATP kinetics and contractile function in postischemic myocardium.Am J Physiol Heart Circ Physiol 303, no. 7 (October 1, 2012): H844–52. https://doi.org/10.1152/ajpheart.00268.2012.
Akki A, Su J, Yano T, Gupta A, Wang Y, Leppo MK, et al. Creatine kinase overexpression improves ATP kinetics and contractile function in postischemic myocardium. Am J Physiol Heart Circ Physiol. 2012 Oct 1;303(7):H844–52.
Akki, Ashwin, et al. “Creatine kinase overexpression improves ATP kinetics and contractile function in postischemic myocardium.Am J Physiol Heart Circ Physiol, vol. 303, no. 7, Oct. 2012, pp. H844–52. Pubmed, doi:10.1152/ajpheart.00268.2012.
Akki A, Su J, Yano T, Gupta A, Wang Y, Leppo MK, Chacko VP, Steenbergen C, Weiss RG. Creatine kinase overexpression improves ATP kinetics and contractile function in postischemic myocardium. Am J Physiol Heart Circ Physiol. 2012 Oct 1;303(7):H844–H852.

Published In

Am J Physiol Heart Circ Physiol

DOI

EISSN

1522-1539

Publication Date

October 1, 2012

Volume

303

Issue

7

Start / End Page

H844 / H852

Location

United States

Related Subject Headings

  • Up-Regulation
  • Phosphocreatine
  • Myocardium
  • Myocardial Reperfusion Injury
  • Myocardial Ischemia
  • Myocardial Contraction
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Male