Inhibiting SLC38A2 lowers blood pressure in rodent models of hypertension

作者：Chunxiu Du, Hu Xu, Wenqian Zhao, Liping Jiao, Yanghui Chen, Xiaowan Sun, Mingxin Cao, Yufei Zhang, Yanlin Guo, Rongfang Qiao, Fang Ye, Yating Wang, Lan Ye, Lihong Chen, Dao Wen Wang, Youfei Guan, Xiaoyan Zhang · 发表于：Science Translational Medicine · 年份：2025 · DOI：10.1126/scitranslmed.adt5947 · 被引用次数：2 · 研究领域：Ion Transport and Channel Regulation、Single-cell and spatial transcriptomics、Epigenetics and DNA Methylation

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 Slc38a2 gene knockout ( Slc38a2 △EC ) exhibited reduced blood pressure compared with wild-type controls. Single-cell RNA sequencing analysis revealed enhanced NO biosynthesis in the ECs of the Slc38a2 △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 SLC38A2 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.