Myofibrillar Ca2+ sensitization predominantly enhances function and mechanical efficiency of stunned myocardium.

Soei, Loe Kie; Sassen, L. M. A.; Fan, Dongsheng; Veen, Theo van; Krams, Rob; Verdouw, Pieter D.

doi:10.1161/01.cir.90.2.959

Cited by 62 publications

(42 citation statements)

References 46 publications

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“…However, the pathophysiology of stunning in the pig appears to principally relate to altered calcium transients, rather than myofilament defects (20). On the other hand, one prior study using an alternative sensitizer reported enhanced responsiveness in stunned myocardium (39). However, substantial differences in heart rate with this agent may have contributed to this difference.…”

Section: Discussionmentioning

confidence: 99%

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

Soergel

Georgakopoulos

Stull

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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. 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...

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Section: Discussionmentioning

confidence: 99%

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

Soergel

Georgakopoulos

Stull

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…Others have hypothetized that especially during the late reperfusion phase, a decreased Ca 2+ sensitivity of myofilaments is involved in the contractile dysfunction, although mechanism(s) involved in the alteration of Ca 2+ activation of contractile apparatus were not provided [5]. This hypothesis of decreased Ca 2+ sensitivity is supported by a recent study from our laboratory in which we have shown that the Ca 2÷ sensitizing agent EMD 60263, which is devoid of phosphodiesterase inhibitor properties, restored segment length shortening and mechanical efficiency of stunned porcine myocardium, while exerting a negligible effect on the not stunned myocardium [49].…”

Section: Myocardial Stunningmentioning

confidence: 90%

“…In a recent report, Opie described as the two likely causes of stunning during the very early reperfusion phase excess of cystolic Ca 2÷ and the formation of free radicals [49]. For instance, it was shown that intracoronary Ca 2÷ infusions during stunning could restore the contractility [47].…”

Section: Myocardial Stunningmentioning

confidence: 99%

Involvement of the sarcoplasmic reticulum calcium pump in myocardial contractile dysfunction: Comparison between chronic pressure-overload and stunning

Sharma

Verdouw

Lamers

1994

Cardiovasc Drug Ther

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Summary. Acute as well as chronic forms of heart failure involve mechanical dysfunction during systole and/or diastole. The rapid Ca 2+ release from and Ca ~+ reuptake into the tubuli of the sarcoplasmic reticulum are processes that critically determine normal systolic and diastolic myocardial function, which explains why in the last fifteen years so much attention has been paid to understand the performance of the sarcoplasmic reticulum Ca 2+ pump during myocardial contractile dysfunction. In this communication we have reviewed the literature data on sarcoplasmic reticulum Ca 2+ pump function in the chronically pressure-overloaded hypertrophied and stunned (post-ischemic reversibly injured) myocardium in the light of some new data from our laboratory. Results on the pressure-overloaded hypertrophied myocardium provide evidence that impaired relaxation is most likely due to a low capacity of the sarcoplasmic reticulum to pump Ca 2+, a consequence of a lower density of Ca2+-pumping sites within the sarcotubular membranes. Contractile dysfunction in stunned myocardium is accompanied by an upregulation of the sarcoplasmic reticulum Ca ~ + ATPase gene resulting in a slight increase of the Ca2 + pumping activity. The latter increase is likely an adaptive response of the reversibly injured myocardium which may contribute to the slow recovery of contractile function.Cardiovasc Drugs Ther 1994;8:461-468 Key Words. sarcoplasmic reticulum, Ca ~+ pump, hypertrophy, stunning, cardiac failureNormal systolic and diastolic function of the heart requires the release and reuptake of Ca 2+. The contractile state of the heart can be altered by two mechanisms which are both Ca 2+ dependent: changes in the availability of Ca ~÷ to the contractile proteins and changes in the responsiveness of the contractile proteins to activation by intracellular Ca 2+ [1]. The availability of intracellular Ca ~÷ is regulated by the sarcolemma (SL) and sarcoplasmic reticulum (SR) and the Ca 2+ responsiveness is controlled by the myofilaments and regulatory troponin-tropomyosin complex. Excitation-contraction (E-C) coupling is initiated when Ca 2+ channels are opened by depolarization of SL permitting Ca 2+ to enter the cytoplasm. This small Ca 2+ influx induces the release of a much larger quantity of activated Ca 2÷ from the intraeellutar stores in the SR [2,3]. The released Ca 2+ interacts with troponin C, which is part of the regulatory complex of the myofilaments, thereby initiating cardiac contraction. Relaxation starts when Ca 2+ is sequestered by the SR Ca 2+ pump, so that Ca2 ÷ dissociates from the contractile apparatus. Abnormal handling of intracellutar Ca ~+ at any of the steps in E-C coupling can cause cardiae contractile dysfunction and leads to failure. The signalling function of Ca 2+ demands a very low ionic concentration of Ca 2+ inside the myocardial cells (about 10,000 fold lower than outside) and significant changes can therefore be achieved easily. During each depolarization only a very small amount of Ca ~* entering the cell...

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“…Despite numerous efforts, the cellular mechanism of myocardial stunning is not fully understood [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Stunned myocardium remains responsive to positive inotropic agents such as catecholamines [2], increased extracellular Ca 2+ concentration [3], phosphodiesterase III (PDE III) inhibitors (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Bezstarosti

Soei

Verdouw

et al. 1997

Molecular and Cellular Biochemistry

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Previously we showed in an in situ porcine model that the thiadiazinone derivative [+]EMD 60263, a Ca 2+ sensitizer without phosphodiesterase III inhibitory properties, increased contractility more profoundly in stunned than in non-stunned myocardium. This finding was consistent with the observed leftward shifts of the pCa 2+ /Mg 2+ -ATPase curves of isolated myofibrils induced by [+]EMD 60263. The aim of the present investigation was to study the possible involvement of protein kinase C in the mechanism of reduced Ca 2+ responsiveness of myofilaments during stunning. No differences were observed in the maximal activity of the Ca 2+ -stimulated Mg 2+ -ATPase and in the pCa 50 of myofibrils isolated from non-stunned and stunned myocardium. After phosphorylation with [gamma-32 P]-ATP and excess of purified rat brain protein kinase C, the myofibrils were separated on sodiumdodecylsulphate-polyacrylamide gelectrophoresis and the 32 P incorporation counted by the Molecular Imager. Ca 2+ / phosphatidylserine/sn-1,2 diolein-dependent 32 P incorporation catalyzed by excess of purified rat brain protein kinase C in C-protein, TnT and TnI subunits did not show any differences between myofibrils from non-stunned and stunned myocardium. However, protein kinase C-induced phosphorylation of myofibrils isolated from ventricular myocardium of sham-operated pigs resulted in a marked leftward shift of the pCa 50 from 6.03 ± 0.04 to 6.44 ± 0.06 (p < 0.05), while porcine heart cyclic AMP-dependent protein kinase-induced phosphorylation resulted in an expected small rightward shift to 5.97, although statistical significance was not reached. Protein kinase C-induced phosphorylation also stimulated (80%) the maximal myofibrillar Mg 2+ -ATPase activity.[+]EMD 60263 (3 µM) produced a leftward shift of the myofibrillar pCa 2+ /Mg 2+ -ATPase curve which was unaffected by prior protein kinase C-induced phosphorylation. In conclusion, the findings with isolated myofibrils from myocardium of anaesthetized open-chest pigs indicate that protein kinase C might be involved in the mechanism of reduced Ca 2+ responsiveness of myofilaments in stunned myocardium. However, at this stage no differences could be found between the maximal activity of the Ca 2+ -stimulated Mg 2+ -ATPase, the pCa 50 and the degree of phosphorylation of myofibrils isolated from stunned and non-stunned myocardium. (Mol Cell Biochem 176: 211-218, 1997) Key words: cardiac myofibrils, cardiac sarcoplasmic reticulum, human, pig, Ca 2+ stimulated Mg 2+ -ATPase, thiadiazinone derivatives, stunningAbbreviations: ATPase -Adenosine-5′-triphosphatase; EGTA -ethylene glycol bis(β-aminoethylether) N,N,N′,N′-tetraacetic acid; DTT -dithiothreitol; MOPS -4-morpholino-propane sulfonic acid; P i -inorganic phosphate; PS -phosphatidylserine; DG -sn-1,2 diolein; SDS-PAAGE -sodiumdodecylsulphate-polyacrylamide gelectrophoresis; PMSF -phenylmethanesulfonylfluoride; PDE III -phosphodiesterase III; LADCA -left anterior descending coronary artery; LCXCA -left circumflex coronary artery; Tn...

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Myofibrillar Ca2+ sensitization predominantly enhances function and mechanical efficiency of stunned myocardium.

Abstract: Calcium sensitization affects function and mechanical efficiency of stunned myocardium more profoundly than of not-stunned myocardium, lending support to the hypothesis that Ca2+ desensitization of the myofibrils is involved in myocardial stunning.

Cited by 62 publications

References 46 publications

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

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

Involvement of the sarcoplasmic reticulum calcium pump in myocardial contractile dysfunction: Comparison between chronic pressure-overload and stunning

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