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

Two alkalinizing mechanisms coexist in cardiac myocytes to maintain intracellular pH: sodium/bicarbonate cotransporter (electroneutral isoform NBCn1 and electrogenic isoform NBCe1) and sodium/proton exchanger (NHE1). Dysfunction of these transporters has previously been reported to be responsible for the development of cardiovascular diseases. The aim of this study was to evaluate the contribution of the downregulation of the NBCe1 to the development of cardiac hypertrophy. To specifically reduce NBCe1 expression, we cloned shRNA into a cardiotropic adeno-associated vector (AAV9-shNBCe1). After 28 days of being injected with AAV9-shNBCe1, the expression and the activity of NBCe1 in the rat heart were reduced. Strikingly, downregulation of NBCe1 causes significant hypertrophic heart growth, lengthening of the action potential in isolated myocytes, an increase in the duration of the QT interval and an increase in the frequency of Ca2+ waves without any significant changes in Ca2+ transients. An increased compensatory expression of NBCn1 and NHE1 was also observed. We conclude that reduction of NBCe1 is sufficient to induce cardiac hypertrophy and modify the electrical features of the rat heart.

Automated summary

There are two alkalinizing mechanisms in cardiac myocytes to maintain intracellular pH: sodium/bicarbonate cotransporter (NBCn1 and NBCe1) and sodium/proton exchanger (NHE1). Dysfunction of these transporters has been linked to cardiovascular diseases. This study aimed to investigate the role of NBCe1 downregulation in cardiac hypertrophy. The researchers used AAV9-shNBCe1 to specifically reduce NBCe1 expression in rat hearts, leading to hypertrophy, altered electrical features, and compensatory upregulation of NBCn1 and NHE1.