Reduced inotropic reserve and increased susceptibility to cardiac ischemia/reperfusion injury in phosphocreatine-deficient guanidinoacetate-N-methyltransferase-knockout mice.
BACKGROUND
The role of the creatine kinase (CK)/phosphocreatine (PCr) energy buffer and transport system in heart remains unclear. Guanidinoacetate-N-methyltransferase-knockout (GAMT-/-) mice represent a new model of profoundly altered cardiac energetics, showing undetectable levels of PCr and creatine and accumulation of the precursor (phospho-)guanidinoacetate (P-GA). To characterize the role of a substantially impaired CK/PCr system in heart, we studied the cardiac phenotype of wild-type (WT) and GAMT-/- mice.


RESULTS
GAMT-/- mice did not show cardiac hypertrophy (myocyte cross-sectional areas, hypertrophy markers atrial natriuretic factor and beta-myosin heavy chain). Systolic and diastolic function, measured invasively (left ventricular conductance catheter) and noninvasively (MRI), were similar for WT and GAMT-/- mice. However, during inotropic stimulation with dobutamine, preload-recruitable stroke work failed to reach maximal levels of performance in GAMT-/- hearts (101+/-8 mm Hg in WT versus 59+/-7 mm Hg in GAMT-/-; P<0.05). (31)P-MR spectroscopy experiments showed that during inotropic stimulation, isolated WT hearts utilized PCr, whereas isolated GAMT-/- hearts utilized P-GA. During ischemia/reperfusion, GAMT-/- hearts showed markedly impaired recovery of systolic (24% versus 53% rate pressure product recovery; P<0.05) and diastolic function (eg, left ventricular end-diastolic pressure 23+/-9 in WT and 51+/-5 mm Hg in GAMT-/- during reperfusion; P<0.05) and incomplete resynthesis of P-GA.


CONCLUSIONS
GAMT-/- mice do not develop hypertrophy and show normal cardiac function at low workload, suggesting that a fully functional CK/PCr system is not essential under resting conditions. However, when acutely stressed by inotropic stimulation or ischemia/reperfusion, GAMT-/- mice exhibit a markedly abnormal phenotype, demonstrating that an intact, high-capacity CK/PCr system is required for situations of increased cardiac work or acute stress.
ten Hove
Michiel
M
Department of Cardiovascular Medicine, University of Oxford, Oxford, England. michiel.tenhove@well.ox.ac.uk
Lygate
Craig A
CA
Fischer
Alexandra
A
Schneider
Jürgen E
JE
Sang
A Elisabeth
AE
Hulbert
Karen
K
Sebag-Montefiore
Liam
L
Watkins
Hugh
H
Clarke
Kieran
K
Isbrandt
Dirk
D
Wallis
Julie
J
Neubauer
Stefan
S
D000818:Animals; D006332:Cardiomegaly / Q000209:etiology; D003402:Creatine Kinase / Q000502:physiology; D004198:Disease Susceptibility; D004734:Energy Metabolism / Q000502:physiology*; D050937:Guanidinoacetate N-Methyltransferase / Q000172:deficiency* / Q000235:genetics; D006334:Heart Function Tests; D006439:Hemodynamics; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D017202:Myocardial Ischemia; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000378:metabolism; D010725:Phosphocreatine / Q000172:deficiency* / Q000502:physiology; D013312:Stress, Physiological
D010725:Phosphocreatine; D050937:Guanidinoacetate N-Methyltransferase; D003402:Creatine Kinase