Induction of angiotensin-converting enzyme and activation of the renin-angiotensin system contribute to 20-hydroxyeicosatetraenoic acid-mediated endothelial dysfunction

Jennifer Cheng, Victor Garcia, Yan Ding, Cheng Chia Wu, Krutanjali Thakar, J R Falck, Errabelli Ramu, Michal Laniado Schwartzman

Research output: Contribution to journalArticle

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Abstract

Objective-20-hydroxyeicosatetraenoic acid (20-HETE) promotes endothelial dysfunction by uncoupling endothelial NO synthase, stimulating O2 production, and reducing NO bioavailability. Moreover, 20-HETE-dependent vascular dysfunction and hypertension are associated with upregulation of the renin-angiotensin system This study was undertaken to examine the contribution of renin-angiotensin system to 20-HETE actions in the vascular endothelium. Methods and Results-In endothelial cells, 20-HETE induced angiotensin-converting enzyme (ACE) mRNA levels and increased ACE protein and activity by 2-to 3-fold; these effects were negated with addition of the 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20 HEDE). 20-HETE induced ACE expression was protein kinase C independent and epidermal growth factor receptor tyrosine kinase and IκB kinase β dependent. ACE short interfering RNA abolished 20-HETE-mediated inhibition of NO production and stimulation of O2 generation, whereas angiotensin II type 1 receptor short interfering RNA attenuated these effects by 40%. 20-HETE-stimulated O2 production was negated by 20-HEDE and was attenuated by lisinopril and losartan. Importantly, 20-HETE-mediated impairment of acetylcholine-induced relaxation in rat renal interlobar arteries was also attenuated by lisinopril and losartan. Conclusion-These results indicate that ACE and angiotensin II type 1 receptor activation contribute to 20-HETE-mediated endothelial cell and vascular dysfunction and further enforce the notion that excessive production of 20-HETE within the vasculature leads to hypertension via mechanisms that include the induction of endothelial ACE, thus, perpetuating an increase in vascular angiotensin which, together with 20-HETE, promotes vascular dysfunction.

Original languageEnglish (US)
Pages (from-to)1917-1924
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume32
Issue number8
DOIs
StatePublished - Aug 2012

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Enzyme Activation
Peptidyl-Dipeptidase A
Renin-Angiotensin System
Lisinopril
Blood Vessels
Angiotensin Type 1 Receptor
Losartan
Small Interfering RNA
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Endothelial Cells
Hypertension
Vascular Endothelium
Angiotensins
Renal Artery
Epidermal Growth Factor Receptor
Nitric Oxide Synthase
Protein-Tyrosine Kinases
Protein Kinase C
Biological Availability
Acetylcholine

Keywords

  • angiotensin II
  • eicosanoids
  • hypertension
  • nitric oxide
  • superoxide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Induction of angiotensin-converting enzyme and activation of the renin-angiotensin system contribute to 20-hydroxyeicosatetraenoic acid-mediated endothelial dysfunction. / Cheng, Jennifer; Garcia, Victor; Ding, Yan; Wu, Cheng Chia; Thakar, Krutanjali; Falck, J R; Ramu, Errabelli; Schwartzman, Michal Laniado.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 32, No. 8, 08.2012, p. 1917-1924.

Research output: Contribution to journalArticle

Cheng, Jennifer ; Garcia, Victor ; Ding, Yan ; Wu, Cheng Chia ; Thakar, Krutanjali ; Falck, J R ; Ramu, Errabelli ; Schwartzman, Michal Laniado. / Induction of angiotensin-converting enzyme and activation of the renin-angiotensin system contribute to 20-hydroxyeicosatetraenoic acid-mediated endothelial dysfunction. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2012 ; Vol. 32, No. 8. pp. 1917-1924.
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abstract = "Objective-20-hydroxyeicosatetraenoic acid (20-HETE) promotes endothelial dysfunction by uncoupling endothelial NO synthase, stimulating O2 production, and reducing NO bioavailability. Moreover, 20-HETE-dependent vascular dysfunction and hypertension are associated with upregulation of the renin-angiotensin system This study was undertaken to examine the contribution of renin-angiotensin system to 20-HETE actions in the vascular endothelium. Methods and Results-In endothelial cells, 20-HETE induced angiotensin-converting enzyme (ACE) mRNA levels and increased ACE protein and activity by 2-to 3-fold; these effects were negated with addition of the 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20 HEDE). 20-HETE induced ACE expression was protein kinase C independent and epidermal growth factor receptor tyrosine kinase and IκB kinase β dependent. ACE short interfering RNA abolished 20-HETE-mediated inhibition of NO production and stimulation of O2 generation, whereas angiotensin II type 1 receptor short interfering RNA attenuated these effects by 40{\%}. 20-HETE-stimulated O2 production was negated by 20-HEDE and was attenuated by lisinopril and losartan. Importantly, 20-HETE-mediated impairment of acetylcholine-induced relaxation in rat renal interlobar arteries was also attenuated by lisinopril and losartan. Conclusion-These results indicate that ACE and angiotensin II type 1 receptor activation contribute to 20-HETE-mediated endothelial cell and vascular dysfunction and further enforce the notion that excessive production of 20-HETE within the vasculature leads to hypertension via mechanisms that include the induction of endothelial ACE, thus, perpetuating an increase in vascular angiotensin which, together with 20-HETE, promotes vascular dysfunction.",
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AU - Cheng, Jennifer

AU - Garcia, Victor

AU - Ding, Yan

AU - Wu, Cheng Chia

AU - Thakar, Krutanjali

AU - Falck, J R

AU - Ramu, Errabelli

AU - Schwartzman, Michal Laniado

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AB - Objective-20-hydroxyeicosatetraenoic acid (20-HETE) promotes endothelial dysfunction by uncoupling endothelial NO synthase, stimulating O2 production, and reducing NO bioavailability. Moreover, 20-HETE-dependent vascular dysfunction and hypertension are associated with upregulation of the renin-angiotensin system This study was undertaken to examine the contribution of renin-angiotensin system to 20-HETE actions in the vascular endothelium. Methods and Results-In endothelial cells, 20-HETE induced angiotensin-converting enzyme (ACE) mRNA levels and increased ACE protein and activity by 2-to 3-fold; these effects were negated with addition of the 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20 HEDE). 20-HETE induced ACE expression was protein kinase C independent and epidermal growth factor receptor tyrosine kinase and IκB kinase β dependent. ACE short interfering RNA abolished 20-HETE-mediated inhibition of NO production and stimulation of O2 generation, whereas angiotensin II type 1 receptor short interfering RNA attenuated these effects by 40%. 20-HETE-stimulated O2 production was negated by 20-HEDE and was attenuated by lisinopril and losartan. Importantly, 20-HETE-mediated impairment of acetylcholine-induced relaxation in rat renal interlobar arteries was also attenuated by lisinopril and losartan. Conclusion-These results indicate that ACE and angiotensin II type 1 receptor activation contribute to 20-HETE-mediated endothelial cell and vascular dysfunction and further enforce the notion that excessive production of 20-HETE within the vasculature leads to hypertension via mechanisms that include the induction of endothelial ACE, thus, perpetuating an increase in vascular angiotensin which, together with 20-HETE, promotes vascular dysfunction.

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KW - eicosanoids

KW - hypertension

KW - nitric oxide

KW - superoxide

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