The specific inhibition of the cardiac electrogenic sodium/bicarbonate cotransporter leads to cardiac hypertrophy.

DI MATTÍA RA; JAQUENOD DE GIUSTI C; BLANCO PG; PORTIANSKY EL; AIELLO EA; ORLOWSKI A

Congreso; XXIV World Congress International Society for Heart Research; 2022

The specific inhibition of the cardiac electrogenic sodium/bicarbonate cotransporter (NBCe1) leads to cardiac hypertrophy Romina Di Mattiaa, Leandro Diaz Zegarraa, Paula Blancob, EnriquePortianskyc, Carlos Valverdea, Luis Gonanoa, Carolina Jaquenod De Giustia, Ernesto Alejandro Aielloa, Alejandro Orlowskia aCardiovascular Research Center, UNLP – CONICET, La Plata, Argentina bFacultad de Veterinaria, Universidad Nacional de La Plata, Servicio de Cardiología, La Plata, Argentina cFacultad de Veterinaria, Universidad Nacional de La Plata, Laboratorio de Análisis de Imágenes, La Plata, ArgentinaIntroductionThe Na+/HCO3− cotransporter (NBC) is one of the main alkalinizing transporters on cardiomyocytes. There are two isoforms of NBC: the electrogenic NBCe1 and the electroneutral NBCn1. Although both isoformsenter Na+ into the cell, NBCe1 contributes with half of Na + per HCO3−, so ithas a major efficiency. We have previously found a reduction of NBCe1activity together with an increased NBCn1 activity in cardiac hypertrophy(CH) models.ObjectivesWe developed an interference RNA cloned in a cardiotropic adenoassociatedviral vector (AAV9-shNBCe1) to study the effect of the specificinhibition of NBCe1 in CH.Materials & methodsWe delivered the virus through a lateral tail vein injection in male 3months old Wistar rats and then performed a series of studies to assess CH,using an AAV9-shControl as control. Data is expressed as means±S.E.M. andis compared with Student's t-test or two-way ANOVA test as needed.ResultsAfter 30 days of injection, we detected a significant reductionon NBCe1 ventricular expression and activity. In addition, we found anincrease in left ventricular mass index obtained by echocardiography onhearts injected with AAV9-shNBCe1 (AAV9-shControl: 1.01 ± 0.1; n = 11;AAV9-shNBCe1*: 1.46 ± 0.11, n = 11; *p b 0.05 vs AAV9-shControl). Thisresult was consistent with cardiomyocytes' cross-sectional area analysisand an increase in ANP mRNA was observed. No differences were found inblood pressure. We also observed a compensatory increase in NBCn1 andNa+/H+ exchanger (NHE1) expressions. Furthermore, we detected anelongation in QTc interval measured through ECG and an elongation inaction potential duration assessed by patch clamp in AAV9-shNBCe1 rats.ConclusionThese results suggest that the CH is developed, at least in part, by thedecrease in NBCe1 expression. A possible proposed mechanism of thisphenomenon is a Na+ overload due to overexpression of NBCn1 and NHE1,which, unlike NBCe1, enter more Na+ per alkaline equivalent into the cell.However, a modification of pH in the dyadic space, where NBCs areparticularly expressed, cannot be ruled out. We described herein for the firsttime that NBCe1 has an impact on in vivo electrical features of the rat heart.