{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:25:42Z","timestamp":1787027142912,"version":"build-2736575974"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Endothelial dysfunction is a major driver for hypertension and diabetes. Chloride (Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      ) is the most abundant anion in vascular endothelial cells (ECs). However, the role of chloride channel or chloride\/proton exchanger ClC-3 in the vascular endothelium and its relationship with endothelium-dependent relaxation remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study aims to explore the role and mechanism of ClC-3 in endothelial dysfunction during hypertension, by using primary cultured human umbilical vein endothelial cells (HUVECs) and ClC-3 knockout mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that AngiotensinII (AngII) treatment significantly upregulated ClC-3 expression and reduced NO levels, while ClC-3 interference increased eNOS phosphorylation. Furthermore, in AngII-infused hypertensive mouse models, ClC-3 knockout significantly increased the phosphorylation level of eNOS and improved vascular relaxation function.\n                      <jats:italic>In vitro<\/jats:italic>\n                      data shows that ClC-3 interacted with eNOS through its oxygenase domain in HUVECs. Moreover, lack of ClC-3 promoted eNOS-Hsp90-Akt complex formation and eNOS disassociation from caveolin-1, and upregulation the phosphorylation of Akt.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our findings suggest that ClC-3 may serve as an important target for hypertension-related endothelial dysfunction, potentially providing new strategies and interventions for the treatment of hypertension and its complications.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1795707","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T06:36:57Z","timestamp":1774593417000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["ClC-3 mediates angiotensin II-induced endothelial dysfunction by inhibiting Akt-Hsp90-eNOS signaling pathway"],"prefix":"10.3389","volume":"17","author":[{"given":"Lei","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University","place":["Guangzhou, China"]},{"name":"Department of Pharmacy, The Second Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-quan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-sheng","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan-hao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-jun","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guozheng","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University","place":["Guangzhou, China"]},{"name":"Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College, Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-hua","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3764","DOI":"10.1093\/eurheartj\/ehaf784.3764","article-title":"Impact of obesity on the association between salt intake and blood pressure in adults with hypertension: findings from cross-sectional and longitudinal analyses","volume":"46","author":"Adachi","year":"2025","journal-title":"Eur. 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