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dc.contributor.authorHe, Dongxu
dc.contributor.authorPan, Qiongxi
dc.contributor.authorChen, Zhen
dc.contributor.authorSun, Chunyuan
dc.contributor.authorZhang, Peng
dc.contributor.authorMao, Aiqin
dc.contributor.authorZhu, Yaodan
dc.contributor.authorLi, Hongjuan
dc.contributor.authorLu, Chunxiao
dc.contributor.authorXie, Mingxu
dc.contributor.authorZhou, Yin
dc.contributor.authorShen, Daoming
dc.contributor.authorTang, Chunlei
dc.contributor.authorYang, Zhenyu
dc.contributor.authorNilius, Bernd
dc.contributor.authoret al.
dc.date.accessioned2020-10-26T04:28:52Z
dc.date.available2020-10-26T04:28:52Z
dc.date.issued2017
dc.identifier.issn1757-4676en_US
dc.identifier.doi10.15252/emmm.201707725en_US
dc.identifier.urihttp://hdl.handle.net/10072/398692
dc.description.abstractThe currently available antihypertensive agents have undesirable adverse effects due to systemically altering target activity including receptors, channels, and enzymes. These effects, such as loss of potassium ions induced by diuretics, bronchospasm by beta‐blockers, constipation by Ca2+ channel blockers, and dry cough by ACEI, lead to non‐compliance with therapies (Moser, 1990). Here, based on new hypertension mechanisms, we explored a new antihypertensive approach. We report that transient receptor potential vanilloid 4 (TRPV4) interacts with Ca2+‐activated potassium channel 3 (KCa2.3) in endothelial cells (ECs) from small resistance arteries of normotensive humans, while ECs from hypertensive patients show a reduced interaction between TRPV4 and KCa2.3. Murine hypertension models, induced by high‐salt diet, N(G)‐nitro‐l‐arginine intake, or angiotensin II delivery, showed decreased TRPV4‐KCa2.3 interaction in ECs. Perturbation of the TRPV4‐KCa2.3 interaction in mouse ECs by overexpressing full‐length KCa2.3 or defective KCa2.3 had hypotensive or hypertensive effects, respectively. Next, we developed a small‐molecule drug, JNc‐440, which showed affinity for both TRPV4 and KCa2.3. JNc‐440 significantly strengthened the TRPV4‐KCa2.3 interaction in ECs, enhanced vasodilation, and exerted antihypertensive effects in mice. Importantly, JNc‐440 specifically targeted the impaired TRPV4‐KCa2.3 interaction in ECs but did not systemically activate TRPV4 and KCa2.3. Together, our data highlight the importance of impaired endothelial TRPV4‐KCa2.3 coupling in the progression of hypertension and suggest a novel approach for antihypertensive drug development.en_US
dc.description.peerreviewedYesen_US
dc.languageEnglishen_US
dc.language.isoeng
dc.publisherEMBO Pressen_US
dc.relation.ispartofpagefrom1491en_US
dc.relation.ispartofpageto1503en_US
dc.relation.ispartofissue11en_US
dc.relation.ispartofjournalEMBO Molecular Medicineen_US
dc.relation.ispartofvolume9en_US
dc.subject.fieldofresearchBiological Sciencesen_US
dc.subject.fieldofresearchMedical and Health Sciencesen_US
dc.subject.fieldofresearchcode06en_US
dc.subject.fieldofresearchcode11en_US
dc.subject.keywordsScience & Technologyen_US
dc.subject.keywordsLife Sciences & Biomedicineen_US
dc.subject.keywordsMedicine, Research & Experimentalen_US
dc.subject.keywordsResearch & Experimental Medicineen_US
dc.subject.keywordsarteryen_US
dc.titleTreatment of hypertension by increasing impaired endothelial TRPV4-KCa2.3 interactionen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationHe, D; Pan, Q; Chen, Z; Sun, C; Zhang, P; Mao, A; Zhu, Y; Li, H; Lu, C; Xie, M; Zhou, Y; Shen, D; Tang, C; Yang, Z; Jin, J; Yao, X; Nilius, B; Ma, X, Treatment of hypertension by increasing impaired endothelial TRPV4-KCa2.3 interaction, EMBO Molecular Medicine, 2017, 9 (11), pp. 1491-1503en_US
dcterms.licensehttps://creativecommons.org/licenses/by/4.0/en_US
dc.date.updated2020-10-26T04:23:30Z
dc.description.versionVersion of Record (VoR)en_US
gro.rights.copyright© 2017 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.en_US
gro.hasfulltextFull Text
gro.griffith.authorNilius, Bernd


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