CIC   05421
CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
artículos
Título:
Role of CaMKII and ROS in rapid pacing-induced apoptosis
Autor/es:
SEPÚLVEDA MARISA; GONANO LUIS; TOMG. BACK; S.R.WAYNE CHEN; VILA PETROFF MARTÍN
Revista:
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Editorial:
ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD
Referencias:
Lugar: Amsterdam; Año: 2013 p. 135 - 145
ISSN:
0022-2828
Resumen:
Tachycardia promotes cell death and cardiac remodeling, leading to congestive heart failure.However, the underlyingmechanismof
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 thesemoleculesmediate 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 withWortmannin 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.