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Restoring TRPV4-KCa2.3 Coupling to Treat Pulmonary Arterial Hypertension
Shaying Yang1,2, Zhiwei Wang1,2, Teng Yang1,2
1MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, China (S.Y., Z.W., T.Y., Y.L., F.Y., A.M., L.F., X.W., X.M.).
Background:
Dysfunction of endothelial cells manifests early in pulmonary arterial hypertension and represents a critical therapeutic target. Nevertheless, the limited efficacy of single-target interventions underscores the need for innovative strategies that enable precise therapeutic modulation.
Methods:
The TRPV4 (transient receptor potential vanilloid 4)-KCa2.3 (small-conductance calcium-activated potassium channel 3) interaction was validated in experimental pulmonary hypertension mice using co-immunoprecipitation and fluorescence (Förster) resonance energy transfer. Based on structure-guided molecular docking, a small-molecule candidate, JNc-455, was rationally designed.
Results:
Dissociation of the TRPV4-KCa2.3 complex was confirmed by both co-immunoprecipitation and fluorescence (Förster) resonance energy transfer analyses in lung tissues from patients with pulmonary arterial hypertension and experimental pulmonary hypertension mice. Endothelial cell-specific recombinant adeno-associated virus-mediated disruption of the complex promoted both the initiation and progression of pulmonary hypertension in vivo. Guided by these findings, we developed a series of compounds aimed at restoring TRPV4-KCa2.3 coupling. Among them, JNc-455 demonstrated significant therapeutic efficacy without overt toxicity. However, this effect was absent in endothelial TRPV4-deficient mice (TRPV4EC-/-), indicating that the action of JNc-455 critically depends on the structural integrity of the complex.
Conclusions:
This study investigates the critical role of the TRPV4-KCa2.3 complex in pulmonary arterial hypertension and, based on these findings, facilitates drug development and screening, thereby identifying JNc-455 as a promising novel therapeutic candidate for pulmonary arterial hypertension.
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