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1 Pediatrics, University of Illinois at Chicago, Chicago, IL, USA; Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
2 Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
3 Pediatrics, University of Illinois at Chicago, Chicago, IL, USA
* To whom correspondence should be addressed. E-mail: gracea{at}uic.edu.
Alteration in myofilament response to Ca2+ is a major mechanism for depressed cardiac function after ischemia-reperfusion dysfunction(I/R). We tested the hypothesis that hearts with increased myofilament response to Ca2+ are less susceptible to I/R. In one approach, we studied transgenic mice (TG) with a constitutive increase in myofilament Ca2+-sensitivity in which the adult form of cardiac troponin I (cTnI) is stoichiometrically replaced with the embryonic/neonatal isoform, slow skeletal TnI (ssTnI). We also studied mouse hearts with EMD 57033, which acts specifically to enhance myofilament response to Ca2+. We subjected isolated, perfused hearts to an I/R protocol consisting of 25 min of no-flow ischemia followed by 30 min of reperfusion. After I/R, developed pressure and rates of pressure change were significantly depressed and end diastolic pressure was significantly elevated in non-transgenic (NTG) controls. These changes were significantly blunted in TG hearts and in NTG hearts perfused with EMD 57033 during reperfusion with function returning to nearly baseline levels. Ca2+ - and cross-bridge dependent activation, protein breakdown, and phosphorylation in detergent extracted fiber bundles were also investigated. Following I/R NTG fiber bundles exhibited a significant depression of cross-bridge dependent activation and Ca2+-activated tension and length dependence of activation which were not evident in the TG preparations. Only NTG hearts demonstrated a significant increase in cTnI phosphorylation after I/R. Our results support the hypothesis that specific increases in myofilament Ca2+ sensitivity are able to diminish the effect of I/R on cardiac function.
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