Enhancing myofilament response to Ca2+ via transgenic ssTnI expression or EMD-57033 significantly blunted the depression of cardiac function after ischemia-reperfusion in isolated murine hearts.
Does specific enhancement of myofilament response to Ca2+ protect murine myocardium against ischemia-reperfusion dysfunction?
Specific increases in myofilament Ca2+ sensitivity protect murine myocardium against ischemia-reperfusion dysfunction.
Alteration in myofilament response to Ca2+ is a major mechanism for depressed cardiac function after ischemia-reperfusion (I/R) dysfunction. We tested the hypothesis that hearts with increased myofilament response to Ca2+ are less susceptible to I/R. In one approach, we studied transgenic (TG) mice 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 nontransgenic (NTG) control hearts. 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. After I/R NTG fiber bundles exhibited a significant depression of cross bridge-dependent activation and Ca2+-activated tension and length dependence of activation that were not evident in TG preparations. Only NTG hearts demonstrated a significant increase in cTnI phosphorylation. Our results support the hypothesis that specific increases in myofilament Ca2+ sensitivity are able to diminish the effect of I/R on cardiac function.
Arteaga et al. (2005) studied Ischemia-reperfusion dysfunction. Transgenic ssTnI expression or EMD-57033 vs. Nontransgenic control hearts was evaluated on Cardiac function (developed pressure, rates of pressure change, end-diastolic pressure). Enhancing myofilament response to Ca2+ via transgenic ssTnI expression or EMD-57033 significantly blunted the depression of cardiac function after ischemia-reperfusion in isolated murine hearts.