Chronic NHE-1 blockade induces an antiapoptotic effect in the hypertrophied heart

Abstract

Na+/H+ exchanger (NHE-1) inhibition was demonstrated to induce the regression of cardiac hypertrophy (CH) in several experimental models and to inhibit mitochondrial death pathway in “in-vitro” experiments. Since recent reports show that NHE-1 inhibition delays the transition from CH to failure, and apoptosis plays a key role in this process, we investigated the effect of chronic treatment with the NHE-1 blocker cariporide on CH and apoptosis in the SHR. One month of cariporide treatment (30 mg·kg−1·day−1) induced the regression of CH (cardiomyocyte cross-sectional area: 468 ± 20 vs. 285 ± 9 μm2 in untreated and cariporide-treated spontaneously hypertensive rats; P < 0.05). Apoptosis was assessed by TUNEL staining, the expression of Bcl-2, Bax, and activation of caspase-3 and PARP-1 by immunoblot. Cariporide treatment decreased the TUNEL-positive cells, the Bax-to-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 2,239 ± 62 vs. 1,683 ± 85 AU, untreated and cariporide-treated, respectively; P < 0.05). Angiotensin II, a growth factor and apoptotic stimulus, was used to induce O2− production that activated the ERK1/2-p90RSK pathway, increasing NHE-1 phosphorylation. These effects were prevented by losartan, N-(2-mercaptopropionyl)-glycine, and cariporide. In conclusion, we present data demonstrating that chronic NHE-1 inhibition with cariporide decreases both hypertrophy and apoptosis susceptibility in the spontaneously hypertensive rat heart. The antiapoptotic effect would 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 mitochondrial effect preventing mitochondrial permeability transition pore opening.