Inhibiting SLC38A2 lowers blood pressure in rodent models of hypertension.

Abstract

Hypertension remains a major global health burden with limited effective treatment options. In the present study, the sodium-dependent neutral amino acid transporter SLC38A2 was identified as a regulator of blood pressure (BP) through modulating endothelial nitric oxide (NO) signaling. Here, we show that mice with global and endothelial cell (EC)-specific <i>Slc38a2</i> gene knockout (<i>Slc38a2</i>^△EC) exhibited reduced blood pressure compared with wild-type controls. Single-cell RNA sequencing analysis revealed enhanced NO biosynthesis in the ECs of the <i>Slc38a2</i>^△EC mice. Blockade of endothelial SLC38A2 by its inhibitor methylaminoisobutyric acid (MeAIB) increased NO production through activating the protein kinase B (AKT)-endothelial NO synthase (eNOS) pathway by inhibiting EC uptake of glutamine. Moreover, MeAIB lowered blood pressure in both high-salt and deoxycorticosterone acetate (DOCA)-induced hypertensive mouse and rat models. Last, in two independent population cohorts including a Chinese cohort established by our group and a European cohort from the UK Biobank, the <i>SLC38A2</i> rs1873793 variant was associated with increased risk of hypertension under a recessive model. Collectively, our findings demonstrate that targeting SLC38A2 may represent a therapeutic target for the treatment of hypertension.