Normalization of the calcineurin pathway underlies the regression of hypertensive hypertrophy induced by Na+/H+ exchanger-1 (NHE-1) inhibition

Irene L. Ennis, Carolina D. Garciarena, Eduardo M. Escudero, Néstor G. Pérez, Raúl A. Dulce, María C.Camilión De Hurtado, Horacio E. Cingolani

Research output: Contribution to journalArticle

Abstract

Na+/H+ exchanger-1 (NHE-I) inhibition induces cardiac hypertrophy regression and (or) prevention in several experimental models, although the intracellular events involved remain unclarified. We aimed to determine whether the calcineurin/NFAT pathway mediates this effect of NHE-1 inhibitors. Spontaneously hypertensive rats (SHR) with cardiac hypertrophy were treated with the NHE-1 inhibitors cariporide and BIIB723 for 30 days. Wistar rats served as normotensive controls. Their hearts were studied by echocardiography, immunoblotting, and real-time RT-PCR. Cytoplasmic Ca 2+ and calcineurin Aβ expression were measured in cultured neonatal rat ventricular myocytes (NRVM) stimulated with endothelin-1 for 24 h. NHE-1 blockade induced cardiac hypertrophy regression (heart mass/body mass = 3.63 ± 0.07 vs. 3.06 ± 0.05 and 3.02 ± 0.13 for untreated vs. cariporide- and BIIB723-treated SHR, respectively; p < 0.05) and decreased myocardial brain natriuretic peptide, calcineurin Aβ, and nuclear NFAT expressions. Echocardiographic evaluation demonstrated a reduction in left ventricular wall thickness without changes in cavity dimensions or a significant decrease in blood pressure. NHE-1-inhibitor treatment did not affect myocardial stiffness or endocardial shortening, but increased mid-wall shortening, suggesting that a positive inotropic effect develops after hypertrophy regression. Cariporide normalized the increased diastolic Ca 2+ and calcineurin Aβ expression observed in ET-1-stimulated NRVM. In conclusion, our data suggest that inactivation of calcineurin/NFAT pathway may underlie the regression of cardiac hypertrophy induced by NHE-1 inhibition.

Original languageEnglish (US)
Pages (from-to)301-310
Number of pages10
JournalCanadian Journal of Physiology and Pharmacology
Volume85
Issue number3-4
DOIs
StatePublished - Mar 1 2007

Keywords

  • Calcineurin
  • Cardiac hypertrophy
  • NHE-1

ASJC Scopus subject areas

  • Physiology
  • Pharmacology
  • Physiology (medical)

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    Ennis, I. L., Garciarena, C. D., Escudero, E. M., Pérez, N. G., Dulce, R. A., De Hurtado, M. C. C., & Cingolani, H. E. (2007). Normalization of the calcineurin pathway underlies the regression of hypertensive hypertrophy induced by Na+/H+ exchanger-1 (NHE-1) inhibition. Canadian Journal of Physiology and Pharmacology, 85(3-4), 301-310. https://doi.org/10.1139/Y06-072