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L Rappaport, Ischemia–reperfusion associated myocardial contractile dysfunction may depend on Ca2+-activated cytoskeleton protein degradation, Cardiovascular Research, Volume 45, Issue 4, March 2000, Pages 810–812, https://doi.org/10.1016/S0008-6363(99)00420-4
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See article by Papp et al. [9] (pages 981–993) in this issue.
1 Introduction
Postischemic dysfunction, or myocardial stunning, is defined as ‘the mechanical dysfunction that persists after reperfusion despite the absence of irreversible damage and restoration of normal or near normal coronary flow’ (for a review, see Ref. [1]). Myocardial stunning may be considered as a relatively mild, sublethal injury that must be distinguished from myocardial infarction. It is generally admitted that myocardial stunning is a multifactorial process, that mostly depends on two major mechanisms: (1) generation of oxygen radicals, (2) calcium overload, both being probably involved in the process (for review, see Ref. [1]).
The calcium hypothesis may explain many key features of the stunned myocardium. It has been postulated that calcium overload during reflow triggers myofilament dysfunction which uncouples excitation from contraction, so that for any given calcium transient, the myocardium generates less force [2].
A variety of biochemical abnormalities have been reported to explain the sustained, but reversible, myocardial contractile dysfunction that occurs after reperfusion. Immunonoblotting and SDS–PAGE analysis have permitted the identification of subtle Ca2+-dependent changes in the amount of myofibrillar proteins. Elevated [Ca2+]i during ischemia and during the initial reperfusion period have long-lasting after effects by activating Ca2+-dependent proteases, which could partially degrade contractile proteins [3]. Myofilament dysfunction would depend on protein degradation, the extent to which increases with the severity of injury, the major functional damage occurring on reperfusion [2]. Indeed, in stunned rat myocardium depression of myofilament function has been associated with a Ca2+-dependent degradation of α-actinin, a myofilament-associated scaffolding protein distributed at the level of the Z line [4] and of a thin filament regulatory protein, troponin I (TnI) [5]. The exact role of these changes in force generation is still unknown. Loss of α-actinin from myofilaments may inhibit the myosin ATPase activity and result in decreased contractility [6]. According to Gao et al. [7] alterations in the myofilaments themselves are entirely responsible for decrease in Ca2+ sensitivity. However, other myofibrillar proteins, such as TNT, myosin light chain-1, MLC1, are also degraded as a result of longer ischemia followed by reperfusion [2]. Moreover, calcium overload induces cross-linking between troponins and other cardiac proteins [8]. Finally, neither light nor electron microscopy examination have revealed clear histological damage and the factors responsible for the decrease in myofilament Ca2+ responsiveness in stunned myocardium are not clear yet. Taken together, there still exist discrepancies in the literature as to the precise nature of myofilament dysfunction which may be due to proteolytic injury to the contractile proteins and/or to oxyradical-mediated covalent modifications.
