Augmented systolic response to the calcium sensitizer EMD-57033 in a transgenic model with troponin I truncation

Abstract

. Augmented systolic response to the calcium sensitizer EMD-57033 in a transgenic model with troponin I truncation. Am J Physiol Heart Circ Physiol 286: H1785-H1792, 2004. First published December 23, 2003 10.1152/ ajpheart.00170.2003.-Myocardial stunning is a form of acute reversible cardiac dysfunction that occurs after brief periods of ischemia and reperfusion. In several animal models, stunning is associated with proteolytic truncation of troponin I (TnI). Mice expressing the same proteolytic TnI fragment ] demonstrate cardiac depression with a decreased maximal calcium-activated tension. We therefore hypothesized preferential improvement in mice expressing treated with the calcium-sensitizing drug EMD-57033. and nontransgenic myofibrils exhibited significant sensitization to calcium in Mg-ATPase assays after EMD-57033 exposure. However, only transgenic myofibrils exhibited an increase in maximal activity (P ϭ 0.023). EMD-57033 also increased maximal calcium-activated force in TnI-(1-193) muscle, such that it was comparable to nontransgenic cardiac muscle. EMD-57033 enhanced in vivo systolic function modestly in controls but had a marked effect in transgenic mice, with an almost threefold greater leftward shift of the end-systolic pressure-volume relation (P ϭ 0.0005). These data indicate a targeted efficacy of EMD-57033 in offsetting the contractile defect in TnI-(1-193) mice, and this may have therapeutic implications in models displaying this myofilament defect. myocardial stunning; inotropic agents; contractile function; heart failure MYOCARDIAL STUNNING IS A FORM of acute reversible cardiac dysfunction that occurs after brief periods of ischemia and reperfusion (2, 3). Although the pathophysiology of stunning is multifactorial, evidence has accumulated that partial proteolysis of troponin I (TnI) can play a role (10,28,46,48). A similar TnI truncation has been observed in the myocardium of humans undergoing cardiac surgery for ischemic disease and in humans with end-stage ischemic cardiomyopathy (29,31,33). TnI proteolysis is not observed in all models of myocardial stunning, however, particularly in regional models of stunning in dogs and pigs (8,27,43). To further define the pathophysiological consequences of this truncation, we generated transgenic mice expressing a mutated TnI that mimicked the major proteolytic fragment demonstrated in animal models of cardiac stunning (31). Hearts from these animals displayed depressed systolic function and decreased maximal calcium-activated tension, suggesting possible targeted responsiveness to a calcium-sensitizing agent. Regardless of its generalizability to the pathophysiology of myocardial stunning, the model is valuable, inasmuch as it reflects contractile dysfunction associated with altered regulatory thin-filament proteins.The present study therefore addressed whether the molecular defect in transgenic TnI-(1-193) mice is preferentially amenable to a calcium sensitizer. We employed the thiadiazinone compound EMD-57033, which influences troponin C (TnC...

Interaction of cardiac troponin with cardiotonic drugs: A structural perspective

“…Furthermore, studies with open chest pig hearts stressed by a stunning protocol, also demonstrated an improvement of contractility with improved mechanical efficiency [79]. A related study has shown that EMD 57033 is potently effective in acutely restoring systolic function in a mouse model harboring a proteolytic truncation of cTnI, cTnI , associated with myocardial stunning [80]. Taken together, these studies indicate that the potential undesirable effects of EMD 57033, such as diastolic abnormalities and impaired relaxation, may not be a problem after all.…”

Pressure-volume relation analysis of mouse ventricular function

“…Second, a quantitation of shifts of these relations to acute interventions may be misleading when based solely on slope, particularly if the data are nonlinear. As depicted in prior studies (28,40) and in Fig. 4, differences between nonlinear ESPVRs can easily be assessed by an area defined between them.…”

Mechanisms and Use of Calcium-Sensitizing Agents in the Failing Heart

“…Changes of this nature are observed if the cross-bridge force generation is itself altered, as has been observed with changes in redox state, with proteolytic cleavage of TnI in postischemic stunned myocardium, and with sensitizers such as EMD-50733. 6 The extent to which such upward shifts occur at low calcium levels might again exacerbate diastolic effects. Lastly, a sensitizer may display Ca 2ϩ -dependent changes, so that effects at lower calcium concentrations are minimized, whereas shifts in the forceCa 2ϩ relation at systolic levels of calcium are manifest (type C).…”

“…Clinical development was ultimately halted because of bioavailability limitations, but experimental studies provided many useful insights into the general drug class as noted in Figures 2 and 5. A recent further finding revealed greater potency of EMD-57033 in a mouse model in which a truncated TnI was overexpressed to mimic proteolytic changes reported in myocardial stunning, 6,64 which suggests that such drugs may be particularly suited to diseases with abnormal Ca 2ϩ sensitivity from altered regulatory thin-filament proteins, This would likely depend on the precise mechanism of action of the agent.…”