title: Normalization of the calcineurin pathway underlies the regression of hypertensive hypertrophy induced by Na+/H+ exchanger-1 (NHE-1) inhibition.
abstract: Na+/H+ exchanger-1 (NHE-1) 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 Ca2+ and calcineurin Abeta 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 Abeta, 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 Ca2+ and calcineurin Abeta expression observed in ET-1-stimulated NRVM. In conclusion, our data suggest that inactivation of calcineurin/NFAT pathway may underlie the regression of cardiac hyper-trophy induced by NHE-1 inhibition.
authors.affiliation: Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Calle 60 y 120, 1900 La Plata, Argentina. iennis@atlas.med.unlp.edu.ar
authors.forename: Irene L
authors.initials: IL
authors.lastname: Ennis
authors.forename: Carolina D
authors.initials: CD
authors.lastname: Garciarena
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Escudero
authors.forename: Néstor G
authors.initials: NG
authors.lastname: Pérez
authors.forename: Raúl A
authors.initials: RA
authors.lastname: Dulce
authors.forename: María C
authors.initials: MC
authors.lastname: Camilión de Hurtado
authors.forename: Horacio E
authors.initials: HE
authors.lastname: Cingolani
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism*; D002478:Cells, Cultured; D006146:Guanidines / Q000494:pharmacology; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; C522118:BIIB 723; D006146:Guanidines; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; C452850:Slc9a1 protein, rat; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C495963:natriuretic peptide precursor type B, rat; D020097:Natriuretic Peptide, Brain; C093373:cariporide; D019703:Calcineurin; D002118:Calcium