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

DI MATTÍA RA; JAQUENOD DE GIUSTI, C; BLANCO P; PORTIANSKY E; AIELLO EA; ORLOWSKI A

Virtual

Congreso; XXVII Congreso Argentino de Hipertensión Arterial; 2021

Introduction: The Na+/HCO3- cotransporter (NBC) is one of the main alkalinizing transporters in cardiomyocytes. There are two isoforms of NBC in the heart: the electrogenic NBCe1 and the electroneutral NBCn1. Although both isoforms enters Na+ and HCO3- into the cell, NBCe1 contributes with half of Na+ per HCO3-, exhibiting better efficiency. We have previously reported that there is a reduction of NBCe1 activity together with an increased NBCn1 activity in the cardiac hypertrophy (CH) of the spontaneously hypertensive rats (SHR).Aims: As we were previously unable to demonstrate the exact cause-consequence involvement of NBC isoforms in the development of CH, we developed an interference RNA cloned in a cardiotropic adeno-associated vector (shNBCe1) to study the effect of the specific inhibition of NBCe1 in CH.Experimental design: We delivered the virus through a lateral tail vein injection in male 3 months old Wistar rats and then performed a series of studies to assess CH, using a scramble as control. Results: 30 days after the injection, we made sure that cardiomyocytes were green and that we had a significance reduction on NBCe1 expression. In addition, we compared the left ventricle mass index obtained by echocardiography. We found an increase of LVMI in hearts injected with the shNBCe1. This result was consistent with the analysis of cross-sectional area of the cardiomyocytes. Additionally, some preliminary results indicated a compensatory increase in NBCn1 and Na+/H+ exchanger expression.Conclusion: Overall, these results suggest that CH is developed, at least in part, by the decrease in NBCe1 expression. We propose that this reduction triggers a compensatory response involving the increase of the expression and activity of the remaining alkalinizing transporters. This mechanism would in turn induce the enhancement of intracellular Na+ levels, leading to Ca+2 overload trough Na+/Ca+2 exchanger acting in its reverse mode. Such increase of Ca+2 could lead to CH.