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Creatine kinase-deficient hearts exhibit increased susceptibility to ischemia-reperfusion injury and impaired calcium homeostasis

¹Department of Cardiology, Medizinische Universtätsklinik Würzburg, 97080 Würzburg, Germany; and ²Department of Cardiovascular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, United Kingdom

Submitted 5 November 2003 ; accepted in final form 19 April 2004

The creatine kinase (CK) system is involved in the rapid transport of high-energy phosphates from the mitochondria to the sites of maximal energy requirements such as myofibrils and sarcolemmal ion pumps. Hearts of mice with a combined knockout of cytosolic M-CK and mitochondrial CK (M/Mito-CK^–/–) show unchanged basal left ventricular (LV) performance but reduced myocardial high-energy phosphate concentrations. Moreover, skeletal muscle from M/Mito-CK^–/– mice demonstrates altered Ca²⁺ homeostasis. Our hypothesis was that in CK-deficient hearts, a cardiac phenotype can be unmasked during acute stress conditions and that susceptibility to ischemia-reperfusion injury is increased because of altered Ca²⁺ homeostasis. We simultaneously studied LV performance and myocardial Ca²⁺ metabolism in isolated, perfused hearts of M/Mito-CK^–/– (n = 6) and wild-type (WT, n = 8) mice during baseline, 20 min of no-flow ischemia, and recovery. Whereas LV performance was not different during baseline conditions, LV contracture during ischemia developed significantly earlier (408 ± 72 vs. 678 ± 54 s) and to a greater extent (50 ± 2 vs. 36 ± 3 mmHg) in M/Mito-CK^–/– mice. During reperfusion, recovery of diastolic function was impaired (LV end-diastolic pressure: 22 ± 3 vs. 10 ± 2 mmHg), whereas recovery of systolic performance was delayed, in M/Mito-CK^–/– mice. In parallel, Ca²⁺ transients were similar during baseline conditions; however, M/Mito-CK^–/– mice showed a greater increase in diastolic Ca²⁺ concentration ([Ca²⁺]) during ischemia (237 ± 54% vs. 167 ± 25% of basal [Ca²⁺]) compared with WT mice. In conclusion, CK-deficient hearts show an increased susceptibility of LV performance and Ca²⁺ homeostasis to ischemic injury, associated with a blunted postischemic recovery. This demonstrates a key function of an intact CK system for maintenance of Ca²⁺ homeostasis and LV mechanics under metabolic stress conditions.

aequorin bioluminescence; transgenic mouse

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