Inactivation of RhoA for Hypertension Treatment Through the TRPV4–RhoA–RhoGDI1 Axis

作者：Jiawen Wang, Zhen Yuan, Na Yu, Qian Jiao, Honglei Zhou, Wenjie Liao, Jiwei Shan, Shanshan Ruan, Yi Zhao, Ya Mo, Luyao Qi, Tiejun Li, Jianjun Fu, Bowen Ke, Yufang Xu, Xuhong Qian, Jian Zhang, Zhenjiang Zhao, Shiliang Li, Rui Wang, Honglin Li · 发表于：Circulation · 年份：2025 · DOI：10.1161/circulationaha.124.071884 · 被引用次数：14 · 研究领域：Protein Kinase Regulation and GTPase Signaling、Ion Channels and Receptors、Phosphodiesterase function and regulation

BACKGROUND: The RhoA (Ras homolog family member A) signaling pathway is pivotal in regulating vascular smooth muscle cells (VSMCs) function and blood pressure homeostasis. Current inhibitors of the RhoA signaling pathway are limited in hypertension treatment, suffering from poor efficacy, insufficient specificity, and developmental challenges. METHODS: Cryo-electron microscopy (EM), proximity ligation assay (PLA), and site-directed mutagenesis were used to explore the mechanism of RhoA activity regulation. VSMC, hypertensive animal models, Trpv4 -/- and Arhgdia f/f Myh11-CRE ERT2 (smooth muscle–specific RhoGDI1 knockout) mice were used to investigate the role of the TRPV4 (transient receptor potential cation channel subfamily V member 4)–RhoA–RhoGDI1 (Rho GDP dissociation inhibitor 1) axis in hypertension. RESULTS: AH001 (( R )-1-(3-ethylphenyl) ethane-1,2-diol) was identified as a novel inhibitor of the RhoA signaling pathway. It targets the TRPV4–RhoA–RhoGDI1 axis to effectively sequester inactive RhoA–GDP in the plasma membrane and cytoplasm, which is distinct from typical RhoA inhibition modes. The cryo-EM structure of the TRPV4 AH001 –RhoA complex showed that AH001-bound TRPV4 adopts a closed state with RhoA in an inactive GDP-bound state. Functional studies further revealed that AH001 reduced the pool of active RhoA by enhancing TRPV4–RhoA binding and facilitating RhoGDI1–RhoA interaction in VSMC. This inhibition notably decreased both acute and long-term blood pressure...