CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
Chronic NHE-1 blockade induces an antiapoptotic effect in the hypertrophied heart.
GARCIARENA CD; CALDIZ CI; PORTIANSKY EL; CHIAPPE DE CINGOLANI GE; ENNIS IL
JOURNAL OF APPLIED PHYSIOLOGY
American Physiological Society
Lugar: Bethesda; Año: 2009 vol. 106 p. 1325 - 1331
Na+/H+ exchanger (NHE-1) inhibition was demonstrated to induce the regression of cardiachypertrophy (CH) in several experimental models and to inhibit mitochondrial death pathway inin-vitro experiments. Since recent reports show that NHE-1 inhibition delays the transition fromCH to failure, and apoptosis plays a key role in this process, we investigated the effect of chronictreatment with the NHE-1 blocker cariporide on CH and apoptosis in the SHR.One month of cariporide treatment (30 mg/kg/day) induced the regression of CH (cardiomyocytecross sectional area: 468±20 vs. 285±9 μm2 in untreated and cariporide-treated SHR; p < 0.05).Apoptosis was assessed by TUNEL staining, the expression of Bcl-2, Bax, and activation ofcaspase-3 and PARP-1 by immunoblot. Cariporide treatment decreased the TUNEL- positive cells,the Bax/Bcl-2 ratio (3.16±0.32 vs. 1.70±0.17, untreated and cariporide-treated respectively; p <0.05); caspase-3 and PARP-1 activation (465±62 vs. 260±22 and 2239±62 vs. 1683±85 AU,untreated and cariporide-treated respectively; p < 0.05). Angiotensin II, a growth factor andapoptotic stimulus, was used to induce O2- production that activated the ERK1/2- p90RSK pathwayincreasing NHE-1 phosphorylation. These effects were prevented by losartan, N-(2-mercaptopropionyl)-glycine and by cariporide.In conclusion, we present data demonstrating that chronic NHE-1 inhibition with cariporidedecreases both hypertrophy and apoptosis susceptibility in the SHR heart. The antiapoptotic effectwould be the consequence of two different actions of cariporide: the prevention of cytosolic Na+and Ca2+ overload due to the inhibition of the sarcolemmal NHE-1; and a direct mitochondrialeffect preventing mitochondrial permeability transition pore opening.