Role of CaMKII and ROS in rapid pacing-induced apoptosis

Abstract 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 fa...

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Published in:	Journal of molecular and cellular cardiology Vol. 63; pp. 135 - 145
Main Authors:	Sepúlveda, Marisa, Gonano, Luis A, Back, Tom G, Chen, S.R. Wayne, Vila Petroff, Martin
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-10-2013
Subjects:	Androstadienes - pharmacology Animals Apoptosis Calcium Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism CaMKII Cardiovascular Cell Death Cell Survival Heart failure Mice Mice, Transgenic Myocytes, Cardiac - metabolism Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - metabolism Rats Reactive Oxygen Species - metabolism ROS Signal Transduction - drug effects Tachycardia Tachycardia - metabolism Heart failure Tachycardia CaMKII Calcium ROS Apoptosis
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Summary:	Abstract 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, Ca 2 + 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 Ca 2 + 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 Ca 2 + release, and ruthenium red used to prevent Ca 2 + 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 Ca 2 + release and mitochondrial Ca 2 + 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2828 1095-8584
DOI:	10.1016/j.yjmcc.2013.07.013