CIC   05421
CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Na+/H+ exchanger-1 inhibitors decrease myocardial superoxide production by a direct mitochondrial action.
Autor/es:
GARCIARENA CD; CALDIZ CI; CORREA MV; SCHINELLA GR; MOSCA SM; CHIAPPE DE CINGOLANI GE; CINGOLANI HE; ENNIS IL
Lugar:
Munich, Alemania
Reunión:
Congreso; European Society of Cardiology Congress; 2008
Institución organizadora:
European Society of Cardiology
Resumen:
<!--
/* Style Definitions */
p.MsoNormal, li.MsoNormal, div.MsoNormal
{mso-style-parent:"";
margin:0cm;
margin-bottom:.0001pt;
mso-pagination:widow-orphan;
font-size:12.0pt;
font-family:"Times New Roman";
mso-fareast-font-family:"Times New Roman";}
@page Section1
{size:595.3pt 841.9pt;
margin:70.85pt 3.0cm 70.85pt 3.0cm;
mso-header-margin:35.4pt;
mso-footer-margin:35.4pt;
mso-paper-source:0;}
div.Section1
{page:Section1;}
-->
The
possibility of a direct mitochondrial action of Na+/H+ exchanger-1 (NHE-1)
inhibitors leading to a decrease in reactive oxygen species (ROS) production
was explored in cat cardiac slices. Anion superoxide (O2-) production was
measured by the lucigenin-enhanced chemiluminescence method. Values are the
difference from the non stimulated control (arbitrary units/min/mg dry weight)
after 15 min minutes in the presence of lucigenin.
1nM
angiotensin II induced after 30 min a NADPH oxidase-dependent (NOX) increase in
O2- production (1nM Ang II, 49.6±8.9, n=34; 300μM apocynin, -7.7±17.0, n=7) that was prevented
by three different NHE-1 inhibitors: 10μM cariporide (7.4±6, n=12), 1μM BIIB723 (5.7±13.9, n=3) and 5μM EMD87580 (-2.2±12.1, n=4)
(p<0.05, ANOVA). These drugs were devoid of ROS scavenger activity. The
source of the NOX-dependent O2- released seemed to be the mitochondria through
the "ROS induced-ROS release" mechanism since it was blunted by the
mitochondrial KATP channel (mKATP) blockers 100μM 5-hydroxydecanoate (2.5±14.3, n=10) and 50μM glibenclamide (-20.8±4.9, n=6), by
inhibition of complex I of the electron transport chain with 10μM rotenone (-11.9±23.5, n=8) and the
mitochondrial permeability transition pore (MPTP) by 2μM cyclosporin A (-8.7±9.1, n=4) (p<0.05,
ANOVA). O2- production induced by the opening of mKATP with 100μM diazoxide (53.3±9.3, n=19) was
also prevented by 10μM
cariporide (12.3±5.6, n=5), giving further support to a direct mitochondrial
action of NHE-1 blockers. Cariporide also decreased Ca2+ induced-mitochondrial
swelling by 36.7±3.3% (n=7), approximately to the same extent than 2μM cyclosporin A (41.5±4.4%, n=7) and
10μM bongkrekic acid
(34.2±2.0%, n=6) (p<0.05, ANOVA), without showing any additive effect. Ang
II-increase of O2- stimulated ERK1/2 and p90RSK phosphorylation measured by
Western blot (315±7% and 173±11% respectively vs. non stimulated control, n=4,
P<0.05, ANOVA), and it was also prevented by cariporide (116±25% and 111±13%
respectively, n=4, p<0.05, ANOVA) This gives additional support to the
presence of a direct mitochondrial action of NHE-1 inhibitors preventing ROS
release. We report a direct mitochondrial action of NHE-1 inhibitors that may
explain their beneficial effect in several cardiac diseases such as
ischemia/reperfusion injury and cardiac hypertrophy and failure.