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lüll Inhibition of reverse-mode sodium-calcium exchanger activity and apoptosis by levosimendan in human cardiomyocyte progenitor cell-derived cardiomyocytes after anoxia and reoxygenation Li PC; Yang YC; Hwang GY; Kao LS; Lin CYPLoS One 2014[]; 9 (2): e85909Levosimendan, a known calcium sensitizer with positive inotropic and vasodilating properties, might also be cardioprotective during ischemia-reperfusion (I/R) insult. Its effects on calcium homeostasis and apoptosis in I/R injury remain unclear. Na(+)/Ca(2+) exchanger (NCX) is a critical mediator of calcium homeostasis in cardiomyocytes, with reverse-mode NCX activity responsible for intracellular calcium overload and apoptosis of cardiomyocytes during I/R. We probed effects and underlying mechanisms of levosimendan on apoptosis and NCX activity in cultured human cardiomyocyte progenitor cells (CPC)-derived cardiomyocytes undergoing anoxia-reoxygenation (A/R), simulating I/R in vivo. Administration of levosimendan decreased apoptosis of CPC-derived cardiomyocytes induced by A/R. The increase in reverse-mode NCX activity after A/R was curtailed by levosimendan, and NCX1 was translocated away from the cell membrane. Concomitantly, endoplasmic reticulum (ER) stress response induced by A/R was attenuated in CPC-derived cardiomycytes treated with NCX-targeted siRNA or levosimendan, with no synergistic effect between treatments. Results indicated levosimendan inhibited reverse-mode NCX activity to protect CPC-derived cardiomyocytes from A/R-induced ER stress and cell death.|Adolescent[MESH]|Apoptosis/*drug effects[MESH]|Blotting, Western[MESH]|Cardiotonic Agents/pharmacology[MESH]|Cell Hypoxia[MESH]|Cell Membrane/drug effects/metabolism[MESH]|Cells, Cultured[MESH]|Child[MESH]|Endoplasmic Reticulum Stress/drug effects[MESH]|Female[MESH]|Flow Cytometry[MESH]|HEK293 Cells[MESH]|Humans[MESH]|Hydrazones/*pharmacology[MESH]|Male[MESH]|Microscopy, Confocal[MESH]|Myocytes, Cardiac/cytology/*drug effects/metabolism[MESH]|Oxygen/pharmacology[MESH]|Pyridazines/*pharmacology[MESH]|RNA Interference[MESH]|Simendan[MESH]|Sodium-Calcium Exchanger/*antagonists & inhibitors/genetics/metabolism[MESH]|Stem Cells/*drug effects/metabolism[MESH] |