Inhibition of reverse-mode sodium-calcium exchanger activity and apoptosis by levosimendan in human cardiomyocyte progenitor cell-derived cardiomyocytes after anoxia and reoxygenation.
Levosimendan, 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.
Department of Surgery, Division of Cardiovascular Surgery, China Medical University Hospital, Taichung, Taiwan ; Department of Life Science, Tunghai University, Taichung, Taiwan.
Ping-Chun
PC
Li
Department of Life sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
Ya-Chi
YC
Yang
Department of Life Science, Tunghai University, Taichung, Taiwan.
Guang-Yuh
GY
Hwang
Department of Life sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
Lung-Sen
LS
Kao
Clinical Immunology Center, China Medical University Hospital, Taichung, Taiwan ; College of Medicine, China Medical University, Taichung, Taiwan.
Ching-Yuang
CY
Lin
D000293:Adolescent; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology; D015687:Cell Hypoxia; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D008297:Male; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D034622:RNA Interference; D000077464:Simendan; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism
D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D000077464:Simendan; D010100:Oxygen