Inhibiting SLC38A2 lowers blood pressure in rodent models of hypertension

IF 14.6 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2025-09-03 DOI:10.1126/scitranslmed.adt5947

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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引用次数: 0

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.

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抑制SLC38A2降低高血压啮齿动物模型的血压

高血压仍然是全球主要的健康负担，有效的治疗选择有限。在本研究中，钠依赖性中性氨基酸转运体SLC38A2被确定为通过调节内皮一氧化氮（NO）信号来调节血压（BP）。在这里，我们表明，与野生型对照相比，全球和内皮细胞（EC）特异性Slc38a2基因敲除（Slc38a2△EC）的小鼠表现出降低的血压。单细胞RNA测序分析显示，Slc38a2△EC小鼠EC细胞中NO生物合成增强。内皮细胞SLC38A2的抑制剂MeAIB通过抑制EC对谷氨酰胺的摄取，激活蛋白激酶B (AKT) -内皮细胞NO合成酶（eNOS）通路，从而增加NO的产生。此外，MeAIB在高盐和醋酸脱氧皮质酮（DOCA）诱导的高血压小鼠和大鼠模型中均能降低血压。最后，在两个独立的人群队列中，包括我们小组建立的中国队列和来自英国生物银行的欧洲队列，SLC38A2 rs1873793变体在隐性模型下与高血压风险增加相关。总之，我们的研究结果表明，靶向SLC38A2可能是治疗高血压的一个治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.