Small Interfering RNA Targeting Mitochondrial Calcium Uniporter Improves Cardiomyocyte Cell Viability in Hypoxia/Reoxygenation Injury by Reducing Calcium Overload.
Intracellular Ca2+mishandling is an underlying mechanism in hypoxia/reoxygenation (H/R) injury that results in mitochondrial dysfunction and cardiomyocytes death. These events are mediated by mitochondrial Ca2+(mCa2+) overload that is facilitated by the mitochondrial calcium uniporter (MCU) channel. Along this line, we evaluated the effect of siRNA-targeting MCU in cardiomyocytes subjected to H/R injury. First, cardiomyocytes treated with siRNA demonstrated a reduction of MCU expression by 67%, which resulted in significant decrease in mitochondrial Ca2+transport. siRNA treated cardiomyocytes showed decreased mitochondrial permeability pore opening and oxidative stress trigger by Ca2+overload. Furthermore, after H/R injury MCU silencing decreased necrosis and apoptosis levels by 30% and 50%, respectively, and resulted in reduction in caspases 3/7, 9, and 8 activity. Our findings are consistent with previous conclusions that demonstrate that MCU activity is partly responsible for cellular injury induced by H/R and support the concept of utilizing siRNA-targeting MCU as a potential therapeutic strategy.
Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, NL, Mexico.
Yuriana
Y
Oropeza-Almazán
Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, NL, Mexico.
Eduardo
E
Vázquez-Garza
Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, NL, Mexico.
Héctor
H
Chapoy-Villanueva
Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, NL, Mexico; Centro de Investigación Biomédica, Hospital Zambrano-Hellion, San Pedro Garza-García, NL, Mexico; Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX, USA.
Guillermo
G
Torre-Amione
Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, Monterrey, NL, Mexico; Centro de Investigación Biomédica, Hospital Zambrano-Hellion, San Pedro Garza-García, NL, Mexico.
Gerardo
0000-0003-4731-3293
G
García-Rivas
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D002460:Cell Line; D002470:Cell Survival; D016572:Cyclosporine / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D015220:Calcium Channels; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C034703:mitochondrial calcium uniporter; D016572:Cyclosporine; D002118:Calcium