| Title: | Inhibiting SLC38A2 lowers blood pressure in rodent models of hypertension |
| Journal: | Science Translational Medicine |
| Published: | 3 Sep 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40901922/ |
| DOI: | https://doi.org/10.1126/scitranslmed.adt5947 |
Publication 19577
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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 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.</p>
15 Keywords
- Animals
- Blood Pressure
- Disease Models, Animal
- Endothelial Cells
- Humans
- Hypertension
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Nitric Oxide
- Nitric Oxide Synthase Type III
- Proto-Oncogene Proteins c-akt
- Rats
- Signal Transduction
17 Authors
- 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
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