Abstract
The Ca2+ paradox represents a good model to study Ca2+ overload injury in ischemic heart diseases. We and others have demonstrated that contracture and calpain are involved in the Ca2+ paradox-induced injury. This study aimed to elucidate their roles in this model. The Ca2+ paradox was elicited by perfusing isolated rat hearts with Ca2+-free KH media for 3 min or 5 min followed by 30 min of Ca2+ repletion. The LVDP was measured to reflect contractile function, and the LVEDP was measured to indicate contracture. TTC staining and the quantification of LDH release were used to define cell death. Calpain activity and troponin I release were measured after Ca2+ repletion. Ca2+ repletion of the once 3-min Ca2+ depleted hearts resulted in almost no viable tissues and the disappearance of contractile function. Compared to the effects of the calpain inhibitor MDL28170, KB-R7943, an inhibitor of the Na+/Ca2+ exchanger, reduced the LVEDP level to a greater extent, which was well correlated with improved contractile function recovery and tissue survival. The depletion of Ca2+ for 5 min had the same effects on injury as the 3-min Ca2+ depletion, except that the LVEDP in the 5-min Ca2+ depletion group was lower than the level in the 3-min Ca2+ depletion group. KB-R7943 failed to reduce the level of LVEDP, with no improvement in the LVDP recovery in the hearts subjected to the 5-min Ca2+ depletion treatment; however, KB-R7943 preserved its protective effects in surviving tissue. Both KB-R7943 and MDL28170 attenuated the Ca2+ repletion-induced increase in calpain activity in 3 min or 5 min Ca2+ depleted hearts. However, only KB-R7943 reduced the release of troponin I from the Ca2+ paradoxic heart. These results provide evidence suggesting that contracture is the main cause for contractile dysfunction, while activation of calpain mediates cell death in the Ca2+ paradox.
Highlights
It is well documented that Ca2+ participates in numerous physiological functions in the heart, such as excitation-contraction coupling and excitability [1,2], whereas abnormalities in Ca2+ homeostasis is a common phenomenon that occurs during progressive heart failure [3] and myocardial ischemia/reperfusion injury, i.e., thrombolysis treatment or percutaneous transluminal coronary angioplasty after acute thrombosis formation and restored circulation to the heart following the interruption of flow during open heart surgery [4]
As we had stated previously [20], the 3-min Ca2+ depletion resulted in no viable tissue, as shown by Triphenyltetrazolium chloride (TTC) staining, and an increase in lactate dehydrogenase (LDH) release compared with the control group (Figure 1, A–C)
Treatment with 10 mM KB-R7943, administered 1 min before the Ca2+ depletion, during the Ca2+ depletion, and the first 2 min after the Ca2+ repletion almost completely abolished the tissue injury by the 3-min Ca2+ depletion treatment, with a small myocardial injury area marked by TTC staining and significant decreases in the release of LDH (Figure 1, A–C)
Summary
It is well documented that Ca2+ participates in numerous physiological functions in the heart, such as excitation-contraction coupling and excitability [1,2], whereas abnormalities in Ca2+ homeostasis is a common phenomenon that occurs during progressive heart failure [3] and myocardial ischemia/reperfusion injury, i.e., thrombolysis treatment or percutaneous transluminal coronary angioplasty after acute thrombosis formation and restored circulation to the heart following the interruption of flow during open heart surgery [4]. One of the most apparent changes after repletion of the once Ca2+depleted hearts is diastolic dysfunction, or the development of contracture, which induces physical stress [7,8,9,10]. This aspect is manifested by the formation of contraction bands, sustained cell shortening, or an elevated left ventricle end-diastolic pressure (LVEDP) in the tracing of left ventricle pressure [7,8,9]. In cultured cell models, which are free from mechanical interactions with adjacent cells, suppressing the Na+/ Ca2+ exchanger (NCX) with SEA0400 decreased cell death induced by the Ca2+ paradox [11]. It is possible that other mechanisms are involved in Ca2+ paradox-induced heart injury
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