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.
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