Chronic NHE-1 blockade induces an antiapoptotic effect in the hypertrophied heart.
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.
Garciarena
Carolina D
CD
Fellow of Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina.
Caldiz
Claudia I
CI
Portiansky
Enrique L
EL
Chiappe de Cingolani
Gladys E
GE
Ennis
Irene L
IL
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D006332:Cardiomegaly / Q000188:drug therapy* / Q000473:pathology*; D002467:Cell Nucleus / Q000473:pathology / Q000648:ultrastructure; D006146:Guanidines / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D011918:Rats, Inbred SHR; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000627:therapeutic use*; D013481:Superoxides / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; C452850:Slc9a1 protein, rat; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D051028:bcl-2-Associated X Protein; D013481:Superoxides; D000804:Angiotensin II; C093373:cariporide