Interleukin-6 inhibits endothelial nitric oxide synthase activation and increases endothelial nitric oxide synthase binding to stabilized caveolin-1 in human vascular endothelial cells

Ming Jui Hung, Wen Jin Cherng, Ming Yow Hung, Hsiao Ting Wu, Jong Hwei S Pang

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Objective: We hypothesized a possible mechanism for atherosclerosis in which interleukin-6 (IL-6) might affect the endothelial nitric oxide synthase (eNOS)-caveolin-1 interaction and result in decreased nitric oxide bioavailability in the setting of low-grade inflammation. Methods: Because eNOS and caveolin-1 are crucial for vascular tone control, we studied the effects of IL-6 on the expression and activation of eNOS and caveolin-1 in human vascular endothelial cells. Results: IL-6 inhibited the phosphorylation of eNOS at Ser1177 and the bradykinin-stimulated nitric oxide production; however, eNOS protein expression was not changed. In addition, IL-6 inhibited bradykinin-stimulated Akt phosphorylation at Ser473 and Thr 308 without affecting the Akt protein expression. IL-6 did not alter the mRNA level of caveolin-1; however, the caveolin-1 protein level was significantly increased dose-dependently. The binding of eNOS and caveolin-1 in endothelial cells, as demonstrated by coimmunoprecipitation assay, was increased by IL-6 treatment. IL-6 treatment was found to stabilize caveolin-1 protein and its half-life was estimated to prolong from 7.5 h to longer than 12 h. Furthermore, treatment with PD98059 and short interference RNA of extracellular signal-regulated kinase gene reversed the effects of IL-6 on eNOS and caveolin-1. Conclusion: In addition to decreasing Akt phosphorylation, the results of this study demonstrate, for the first time, the molecular mechanism underlying the effect of IL-6 to decrease the nitric oxide bioavailability by increasing the half-life and, therefore, the protein levels of caveolin-1. The increased caveolin-1 proteins bind more eNOS and consequently decrease eNOS activation by reducing the Ser1177 phosphorylation.

Original languageEnglish
Pages (from-to)940-951
Number of pages12
JournalJournal of Hypertension
Volume28
Issue number5
DOIs
Publication statusPublished - May 2010
Externally publishedYes

Fingerprint

Caveolin 1
Nitric Oxide Synthase Type III
Interleukin-6
Endothelial Cells
Caveolins
Phosphorylation
Nitric Oxide
Bradykinin
Biological Availability
Half-Life
Proteins
Extracellular Signal-Regulated MAP Kinases
RNA Interference
Blood Vessels
Atherosclerosis
Inflammation

Keywords

  • Caveolin-1
  • Endothelial nitric oxide synthase activation
  • Interleukin-6
  • Vascular endothelial cells

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Interleukin-6 inhibits endothelial nitric oxide synthase activation and increases endothelial nitric oxide synthase binding to stabilized caveolin-1 in human vascular endothelial cells. / Hung, Ming Jui; Cherng, Wen Jin; Hung, Ming Yow; Wu, Hsiao Ting; Pang, Jong Hwei S.

In: Journal of Hypertension, Vol. 28, No. 5, 05.2010, p. 940-951.

Research output: Contribution to journalArticle

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T1 - Interleukin-6 inhibits endothelial nitric oxide synthase activation and increases endothelial nitric oxide synthase binding to stabilized caveolin-1 in human vascular endothelial cells

AU - Hung, Ming Jui

AU - Cherng, Wen Jin

AU - Hung, Ming Yow

AU - Wu, Hsiao Ting

AU - Pang, Jong Hwei S

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N2 - Objective: We hypothesized a possible mechanism for atherosclerosis in which interleukin-6 (IL-6) might affect the endothelial nitric oxide synthase (eNOS)-caveolin-1 interaction and result in decreased nitric oxide bioavailability in the setting of low-grade inflammation. Methods: Because eNOS and caveolin-1 are crucial for vascular tone control, we studied the effects of IL-6 on the expression and activation of eNOS and caveolin-1 in human vascular endothelial cells. Results: IL-6 inhibited the phosphorylation of eNOS at Ser1177 and the bradykinin-stimulated nitric oxide production; however, eNOS protein expression was not changed. In addition, IL-6 inhibited bradykinin-stimulated Akt phosphorylation at Ser473 and Thr 308 without affecting the Akt protein expression. IL-6 did not alter the mRNA level of caveolin-1; however, the caveolin-1 protein level was significantly increased dose-dependently. The binding of eNOS and caveolin-1 in endothelial cells, as demonstrated by coimmunoprecipitation assay, was increased by IL-6 treatment. IL-6 treatment was found to stabilize caveolin-1 protein and its half-life was estimated to prolong from 7.5 h to longer than 12 h. Furthermore, treatment with PD98059 and short interference RNA of extracellular signal-regulated kinase gene reversed the effects of IL-6 on eNOS and caveolin-1. Conclusion: In addition to decreasing Akt phosphorylation, the results of this study demonstrate, for the first time, the molecular mechanism underlying the effect of IL-6 to decrease the nitric oxide bioavailability by increasing the half-life and, therefore, the protein levels of caveolin-1. The increased caveolin-1 proteins bind more eNOS and consequently decrease eNOS activation by reducing the Ser1177 phosphorylation.

AB - Objective: We hypothesized a possible mechanism for atherosclerosis in which interleukin-6 (IL-6) might affect the endothelial nitric oxide synthase (eNOS)-caveolin-1 interaction and result in decreased nitric oxide bioavailability in the setting of low-grade inflammation. Methods: Because eNOS and caveolin-1 are crucial for vascular tone control, we studied the effects of IL-6 on the expression and activation of eNOS and caveolin-1 in human vascular endothelial cells. Results: IL-6 inhibited the phosphorylation of eNOS at Ser1177 and the bradykinin-stimulated nitric oxide production; however, eNOS protein expression was not changed. In addition, IL-6 inhibited bradykinin-stimulated Akt phosphorylation at Ser473 and Thr 308 without affecting the Akt protein expression. IL-6 did not alter the mRNA level of caveolin-1; however, the caveolin-1 protein level was significantly increased dose-dependently. The binding of eNOS and caveolin-1 in endothelial cells, as demonstrated by coimmunoprecipitation assay, was increased by IL-6 treatment. IL-6 treatment was found to stabilize caveolin-1 protein and its half-life was estimated to prolong from 7.5 h to longer than 12 h. Furthermore, treatment with PD98059 and short interference RNA of extracellular signal-regulated kinase gene reversed the effects of IL-6 on eNOS and caveolin-1. Conclusion: In addition to decreasing Akt phosphorylation, the results of this study demonstrate, for the first time, the molecular mechanism underlying the effect of IL-6 to decrease the nitric oxide bioavailability by increasing the half-life and, therefore, the protein levels of caveolin-1. The increased caveolin-1 proteins bind more eNOS and consequently decrease eNOS activation by reducing the Ser1177 phosphorylation.

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KW - Endothelial nitric oxide synthase activation

KW - Interleukin-6

KW - Vascular endothelial cells

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