Role of CaMKII and ROS in rapid pacing-induced apoptosis
| Autor: | Martin Vila Petroff, S. R. Wayne Chen, Marisa Noemí Sepúlveda, Thomas G. Back, Luis Alberto Gonano |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Programmed cell death CIENCIAS MÉDICAS Y DE LA SALUD Cell Survival Mice Transgenic Apoptosis Heart failure Medicina Clínica Biology Wortmannin chemistry.chemical_compound Mice Phosphatidylinositol 3-Kinases Internal medicine Ca2+/calmodulin-dependent protein kinase Tachycardia medicine Animals Myocytes Cardiac Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors CaMKII Cell Death Sistemas Cardíaco y Cardiovascular Ryanodine receptor ROS Cell biology Rats Androstadienes Endocrinology chemistry Calcium Cardiology and Cardiovascular Medicine Calcium-Calmodulin-Dependent Protein Kinase Type 2 Reactive Oxygen Species Proto-Oncogene Proteins c-akt Intracellular Signal Transduction |
| Popis: | Tachycardia promotes cell death and cardiac remodeling, leading to congestive heart failure. However, the underlying mechanism of tachycardia- or rapid pacing (RP)-induced cell death remains unknown. Myocyte loss by apoptosis is recognized as a critical factor in the progression to heart failure and simulation of tachycardia by RP has been shown to increase the intracellular levels of at least two potentially proapoptotic molecules, Ca2 + and reactive oxygen species (ROS). However, whether these molecules mediate tachycardia- or RP-induced cell death has yet to be determined. The aim of this study was to examine the subcellular mechanisms underlying RP-induced apoptosis. For this purpose rat ventricular myocytes were maintained quiescent or paced at 0.5, 5 and 8 Hz for 1 hr. RP at 5 and 8 Hz decreased myocyte viability by 58 ± 3% and 75 ± 6% (n = 24), respectively, compared to cells maintained at 0.5 Hz, and increased caspase-3 activity and Bax/Bcl-2 ratio, indicative of apoptosis. RP-induced cell death and apoptosis were prevented when pacing protocols were conducted in the presence of either the ROS scavenger, MPG, or nifedipine to reduce Ca2 + entry or the CaMKII inhibitors, KN93 and AIP. Consistently, myocytes from transgenic mice expressing a CaMKII inhibitory peptide (AC3-I) were protected against RP-induced cell death. Interestingly, tetracaine and carvedilol used to reduce ryanodine receptor (RyR) diastolic Ca2 + release, and ruthenium red used to prevent Ca2 + entry into the mitochondria prevented RP-induced cell death, whereas PI3K inhibition with Wortmannin exacerbated pacing-induced cell mortality. We conclude that CaMKII activation and ROS production are involved in RP-induced apoptosis. Particularly, our results suggest that CaMKII-dependent posttranslational modifications of the cardiac ryanodine receptor (RyR) leading to enhanced diastolic Ca2 + release and mitochondrial Ca2 + overload could be the underlying mechanism involved. We further show that RP simultaneously activates a protective cascade involving PI3K/AKT signaling which is however, insufficient to completely suppress apoptosis. Fil: Sepúlveda, Marisa Noemí. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico la Plata. Centro de Investigaciones Cardiovasculares "dr. Horacio Eugenio Cingolani"; Argentina. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; Argentina Fil: Gonano, Luis Alberto. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico la Plata. Centro de Investigaciones Cardiovasculares "dr. Horacio Eugenio Cingolani"; Argentina. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; Argentina Fil: Back, Tom G.. University Of Calgary; Canadá Fil: Chen, S. R. Wayne. University Of Calgary; Canadá Fil: Vila Petroff, Martin Gerarde. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico la Plata. Centro de Investigaciones Cardiovasculares "dr. Horacio Eugenio Cingolani"; Argentina. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; Argentina |
| Databáze: | OpenAIRE |
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