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

Abstract

OBJECTIVE:

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.

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 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.

CONCLUSIONS:

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.

• Authors: Jennifer Cheng, Victor Garcia, Yan Ding, Cheng-Chia Wu, Krutanjali Thakar, John R Falck, Errabelli Ramu, Michal Laniado Schwartzman
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 32 Issue 8 Pg. 1917-24 (Aug 2012) ISSN: 1524-4636 [Electronic] United States
• PMID: 22723444 (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

Topics

• 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)