Treatment of hypertension by increasing impaired endothelial TRPV4‐KCa2.3 interaction
Abstract The 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+ c...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2017-09-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201707725 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849331968856031232 |
|---|---|
| author | Dongxu He Qiongxi Pan Zhen Chen Chunyuan Sun Peng Zhang Aiqin Mao Yaodan Zhu Hongjuan Li Chunxiao Lu Mingxu Xie Yin Zhou Daoming Shen Chunlei Tang Zhenyu Yang Jian Jin Xiaoqiang Yao Bernd Nilius Xin Ma |
| author_facet | Dongxu He Qiongxi Pan Zhen Chen Chunyuan Sun Peng Zhang Aiqin Mao Yaodan Zhu Hongjuan Li Chunxiao Lu Mingxu Xie Yin Zhou Daoming Shen Chunlei Tang Zhenyu Yang Jian Jin Xiaoqiang Yao Bernd Nilius Xin Ma |
| author_sort | Dongxu He |
| collection | DOAJ |
| description | Abstract The 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. |
| format | Article |
| id | doaj-art-4d6b1e36484944908976f1e4f30c732f |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-4d6b1e36484944908976f1e4f30c732f2025-08-20T03:46:21ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-09-019111491150310.15252/emmm.201707725Treatment of hypertension by increasing impaired endothelial TRPV4‐KCa2.3 interactionDongxu He0Qiongxi Pan1Zhen Chen2Chunyuan Sun3Peng Zhang4Aiqin Mao5Yaodan Zhu6Hongjuan Li7Chunxiao Lu8Mingxu Xie9Yin Zhou10Daoming Shen11Chunlei Tang12Zhenyu Yang13Jian Jin14Xiaoqiang Yao15Bernd Nilius16Xin Ma17School of Medicine, Jiangnan UniversitySchool of Medicine, Jiangnan UniversitySchool of Medicine, Jiangnan UniversitySchool of Medicine, Jiangnan UniversitySchool of Medicine, Jiangnan UniversitySchool of Medicine, Jiangnan UniversitySchool of Medicine, Jiangnan UniversitySchool of Medicine, Jiangnan UniversitySchool of Medicine, Jiangnan UniversitySchool of Medicine, Jiangnan UniversitySchool of Medicine, Jiangnan UniversitySchool of Medicine, Jiangnan UniversitySchool of Medicine, Jiangnan UniversityHeart Centre, Wuxi People's HospitalSchool of Medicine, Jiangnan UniversitySchool of Biomedical Sciences, The Chinese University of Hong KongDepartment Cell Mol Medicine Laboratory Ion Channel Research Campus Gasthuisberg, KU LeuvenSchool of Medicine, Jiangnan UniversityAbstract The 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.https://doi.org/10.15252/emmm.201707725arteryendotheliumhypertensionKCa2.3TRPV4 |
| spellingShingle | Dongxu He Qiongxi Pan Zhen Chen Chunyuan Sun Peng Zhang Aiqin Mao Yaodan Zhu Hongjuan Li Chunxiao Lu Mingxu Xie Yin Zhou Daoming Shen Chunlei Tang Zhenyu Yang Jian Jin Xiaoqiang Yao Bernd Nilius Xin Ma Treatment of hypertension by increasing impaired endothelial TRPV4‐KCa2.3 interaction EMBO Molecular Medicine artery endothelium hypertension KCa2.3 TRPV4 |
| title | Treatment of hypertension by increasing impaired endothelial TRPV4‐KCa2.3 interaction |
| title_full | Treatment of hypertension by increasing impaired endothelial TRPV4‐KCa2.3 interaction |
| title_fullStr | Treatment of hypertension by increasing impaired endothelial TRPV4‐KCa2.3 interaction |
| title_full_unstemmed | Treatment of hypertension by increasing impaired endothelial TRPV4‐KCa2.3 interaction |
| title_short | Treatment of hypertension by increasing impaired endothelial TRPV4‐KCa2.3 interaction |
| title_sort | treatment of hypertension by increasing impaired endothelial trpv4 kca2 3 interaction |
| topic | artery endothelium hypertension KCa2.3 TRPV4 |
| url | https://doi.org/10.15252/emmm.201707725 |
| work_keys_str_mv | AT dongxuhe treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT qiongxipan treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT zhenchen treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT chunyuansun treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT pengzhang treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT aiqinmao treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT yaodanzhu treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT hongjuanli treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT chunxiaolu treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT mingxuxie treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT yinzhou treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT daomingshen treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT chunleitang treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT zhenyuyang treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT jianjin treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT xiaoqiangyao treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT berndnilius treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction AT xinma treatmentofhypertensionbyincreasingimpairedendothelialtrpv4kca23interaction |