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

20-hydroxyeicosatetraenoic acid (20-HETE) promotes endothelial dysfunction by uncoupling endothelial NO synthase, stimulating O(2)(-) 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.
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 O(2)(-) generation, whereas angiotensin II type 1 receptor short interfering RNA attenuated these effects by 40%. 20-HETE-stimulated O(2)(-) 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.
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.
AuthorsJennifer Cheng, Victor Garcia, Yan Ding, Cheng-Chia Wu, Krutanjali Thakar, John R Falck, Errabelli Ramu, Michal Laniado Schwartzman
JournalArteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 32 Issue 8 Pg. 1917-24 (Aug 2012) ISSN: 1524-4636 [Electronic] United States
PMID22723444 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Hydroxyeicosatetraenoic Acids
  • Superoxides
  • Angiotensin II
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Protein-Tyrosine Kinases
  • I-kappa B Kinase
  • Peptidyl-Dipeptidase A
  • Acetylcholine
  • Acetylcholine (pharmacology)
  • Angiotensin II (biosynthesis)
  • Cells, Cultured
  • Endothelial Cells (drug effects, metabolism)
  • Enzyme Induction (drug effects)
  • Humans
  • Hydroxyeicosatetraenoic Acids (pharmacology)
  • I-kappa B Kinase (physiology)
  • Peptidyl-Dipeptidase A (biosynthesis)
  • Protein-Tyrosine Kinases (physiology)
  • Renin-Angiotensin System (drug effects, physiology)
  • Superoxides (metabolism)

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