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1 Pittsburgh Nuclear Magnetic Resonance Center for Biomedical Research, 2 Department of Biological Sciences, and 3 Center for Light Microscope Imaging and Biotechnology, Carnegie Mellon University, Pittsburgh 15213; 4 Cardiovascular Institute of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261; 5 National Institute of Neurological Disease and Stroke, Bethesda, Maryland 20814; 6 Department of Physiology and Biophysics, College of Medicine, University of Illinois, Chicago, Illinois 60612; and 7 Harvard Medical School, Boston, Massachusetts 02115
To determine the in vivo functional significance of troponin I (TnI) protein kinase C (PKC) phosphorylation sites, we created a transgenic mouse expressing mutant TnI, in which PKC phosphorylation sites at serines-43 and -45 were replaced by alanine. When we used high-perfusate calcium as a PKC activator, developed pressures in transgenic (TG) perfused hearts were similar to wild-type (WT) hearts (P = not significant, NS), though there was a 35% and 32% decrease in peak-systolic intracellular calcium (P < 0.01) and diastolic calcium (P < 0.005), respectively. The calcium transient duration was prolonged in the TG mice also (12-27%, ANOVA, P < 0.01). During global ischemia, TG hearts developed ischemic contracture to a greater extent than WT hearts (41 ± 18 vs. 69 ± 10 mmHg, perfusate calcium 3.5 mM, P < 0.01). In conclusion, expression of mutant TnI lacking PKC phosphorylation sites results in a marked alteration in the calcium-pressure relationship, and thus susceptibility to ischemic contracture. The reduced intracellular calcium and prolonged calcium transients suggests that a potent feedback mechanism exists between the myofilament and the processes controlling calcium homeostasis.
calcium; ischemia
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