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 x kg(-1) x day(-1)) induced the regression of CH (cardiomyocyte cross-sectional area: 468 +/- 20 vs. 285 +/- 9 microm(2) 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 O(2)(-) production that activated the ERK1/2-p90(RSK) 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 Ca(2+) overload due to the inhibition of the sarcolemmal NHE-1 and a direct mitochondrial effect preventing mitochondrial permeability transition pore opening.

• Authors: Carolina D Garciarena, Claudia I Caldiz, Enrique L Portiansky, Gladys E Chiappe de Cingolani, Irene L Ennis
• Journal: Journal of applied physiology (Bethesda, Md. : 1985) (J Appl Physiol (1985)) Vol. 106 Issue 4 Pg. 1325-31 (Apr 2009) ISSN: 8750-7587 [Print] United States
• PMID: 19179646 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Guanidines
• Slc9a1 protein, rat
• Sodium-Hydrogen Exchanger 1
• Sodium-Hydrogen Exchangers
• Sulfones
• bcl-2-Associated X Protein
• Superoxides
• Angiotensin II
• cariporide

Topics

• Angiotensin II (pharmacology)
• Animals
• Anti-Arrhythmia Agents (therapeutic use)
• Apoptosis (drug effects)
• Blotting, Western
• Cardiomegaly (drug therapy, pathology)
• Cell Nucleus (pathology, ultrastructure)
• Guanidines (therapeutic use)
• In Situ Nick-End Labeling
• Male
• Mitochondria, Heart (drug effects)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (pathology, ultrastructure)
• Rats
• Rats, Inbred SHR
• Sodium-Hydrogen Exchanger 1
• Sodium-Hydrogen Exchangers (antagonists & inhibitors)
• Sulfones (therapeutic use)
• Superoxides (metabolism)
• bcl-2-Associated X Protein (metabolism)