CIC   05421
CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
INTRACELLULAR SIGNALING PATHWAY OF CARDIAC APOPTOSIS IN THE PREDIABETIC HEART
Autor/es:
SOMMESE L; FEDERICO M; ZANUZZI C; PORTIANSKY E; DEDMAN J; KAETZEL M; WEHRENS XH ; MATTIAZZI A; PALOMEQUE J
Lugar:
Baltimore
Reunión:
Congreso; Biophysical Society 59th Annual meeting; 2015
Institución organizadora:
Biophysical Society
Resumen:
Apoptosis is one of the more important steps leading
to cardiac dysfunction and heart failure (HF), and this disease occurs more
frequently in people with type 2 diabetes than in the general population. However,
in impaired glucose tolerance (IGT), which is the major clinical characteristic
of the prediabetic state, apoptosis has not been previously evaluated in the
heart. Moreover, CaMKII is a well recognized molecule involved in cardiac
apoptosis, hypertrophy, Ca2+ mishandling and arrhythmias. Even less
known is the connection between CaMKII and IGT. The aim of the present study
was to evaluate the presence of cardiac apoptosis in an IGT model and its
putative link with CaMKII activity.
IGT model was induced by a fructose-rich diet
(control, CD; and fructose, FRD; rats or mice). In these animals, echocardiography,
biochemical studies, reactive oxygen species (ROS), Ca2+i
measurements, mitochondrial swelling and mitochondria membrane potential
measurements were performed.
FRD rats showed decreased contractility and increased
hypertrophy (echocardiography) associated with increased CaMKII (P-CaMKII
191.6±18.3%, P-Thr17 of phospholamban 227.6±28.6%), and ROS (185.4±28.6%)
with respect to CD rats (100%). Moreover, the apoptotic ratio Bax/Bcl2 was
increased in FRD vs CD rats (273.6±39.7%) as well as TUNEL positive nuclei.. Isolated
mitochondria from FRD rats showed significant more swelling (DO 0.34±0.05 CD vs
0.53±0.03 FRD) and enhanced membrane depolarization than CD mitochondria.
Moreover, isolated myocytes from FRD rats showed a significant increase in sarcoplasmic
reticulum (SR) Ca2+ leak vs CD myocytes. FRD SR-AIP mice (which express the CaMKII autocamtide inhibitory peptide [AIP]
selectively at the SR membranes) showed less TUNEL positive nuclei than their
matched FRD control mice. In addition, FRD control mice co-treated with fructose and tempol,
a membrane permeable ROS scavenger, also showed less apoptosis than the one induced
by the treatment with fructose alone. SR Ca2+ leak was also
prevented in either FRD SR-AIP mice or CD mice co-treated with tempol. On the
other hand, mitochondria swelling could be also prevented in S2814A mice, which
ryanodine receptor (RyR2) cannot be phosphorylated by CaMKII.
The
results would indicate that the signaling apoptotic cascade in IGT hearts involves
mitochondria damage by SR Ca2+ leak produced by CaMKII-dependent
phosphorylation of RyR2. CaMKII would be activated by both, Ca2+ and
ROS.