The Specific Inhibition of the Cardiac Electrogenic Sodium/Bicarbonate Cotransporter Leads to Cardiac Hypertrophy.

Abstract Two alkalinizing mechanisms coexist in cardiac myocytes in order to maintain the intracellular pH: sodium/bicarbonate cotransporter (electroneutral isoform NBCn1 and electrogenic isoform NBCe1) and sodium/proton exchanger (NHE1). The dysfunction of these transporters has been previously reported as responsible for the development of cardiovascular diseases. The aim of this work was to evaluate the contribution of the downregulation of the NBCe1 to the development of cardiac hypertrophy. To specifically reduce NBCe1, we used shRNA cloned 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, the downregulation of NBCe1 causes significant hypertrophic heart growth, lengthening of the action potential in isolated myocytes, increase in the duration of the QT interval and increase in the frequency of Ca2+ waves without any significant changes in Ca2+ transients. An increased compensatory expression of NBCn1 and NHE1 was also found. We conclude that the reduction of NBCe1 is sufficient to induce cardiac hypertrophy and modify electrical features of the rat heart.