CIC   05421
CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
artículos
Título:
Silencing of cardiac mitochondrial NHE1 prevents mitochondrial permeability transition pore opening.
Autor/es:
VILLA-ABRILLE, MC; CINGOLANI, E; CINGOLANI, HE; ALVAREZ BV
Revista:
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Editorial:
AMER PHYSIOLOGICAL SOC
Referencias:
Año: 2011 p. 1237 - 1251
ISSN:
0363-6135
Resumen:
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Villa-Abrille MC, Cingolani E, Cingolani HE, Alvarez BV.
Silencing of cardiac mitochondrial NHE1 prevents mitochondrial
permeability transition pore opening. Am J Physiol Heart Circ Physiol
300: H1237H1251, 2011. First published February 4, 2011;
doi:10.1152/ajpheart.00840.2010.Inhibition of Na+/H+ exchanger
1 (NHE1) reduces cardiac ischemia-reperfusion (I/R) injury and also
cardiac hypertrophy and failure. Although the mechanisms underlying
these NHE1-mediated effects suggest delay of mitochondrial permeability
transition pore (MPTP) opening, and reduction of mitochondrial-
derived superoxide production, the possibility of NHE1 blockade
targeting mitochondria has been incompletely explored. A short hairpin
RNA sequence mediating specific knock down of NHE1
expression was incorporated into a lentiviral vector (shRNA-NHE1)
and transduced in the rat myocardium. NHE1 expression of mitochondrial
lysates revealed that shRNA-NHE1 transductions reduced mitochondrial
NHE1 (mNHE1) by ~60%, supporting the expression of
NHE1 in mitochondria membranes. Electron microscopy studies corroborate
the presence of NHE1 in heart mitochondria. Immunostaining
of rat cardiomyocytes also suggests colocalization of NHE1 with
the mitochondrial marker cytochrome c oxidase. To examine the
functional role of mNHE1, mitochondrial suspensions were exposed
to increasing concentrations of CaCl2 to induce MPTP opening and
consequently mitochondrial swelling. shRNA-NHE1 transduction reduced
CaCl2-induced mitochondrial swelling by 64± 4%. Whereas
the NHE1 inhibitor HOE-642 (10 mM) decreased mitochondrial
Ca2+-induced swelling in rats transduced with nonsilencing RNAi
(37 ± 6%), no additional HOE-642 effects were detected in mitochondria
from rats transduced with shRNA-NHE1. We have characterized
the expression and function of NHE1 in rat heart mitochondria.
Because mitochondria from rats injected with shRNA-NHE1 present
a high threshold for MPTP formation, the beneficial effects of NHE1
inhibition in I/R resulting from mitochondrial targeting should be
considered.