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


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.
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Jennifer
J
Cheng
Victor
V
Garcia
Yan
Y
Ding
Cheng-Chia
CC
Wu
Krutanjali
K
Thakar
John R
JR
Falck
Errabelli
E
Ramu
Michal Laniado
ML
Schwartzman
D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000096:biosynthesis; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D051550:I-kappa B Kinase / Q000502:physiology; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis*; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D013481:Superoxides / Q000378:metabolism
D006893:Hydroxyeicosatetraenoic Acids; D013481:Superoxides; D000804:Angiotensin II; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D011505:Protein-Tyrosine Kinases; D051550:I-kappa B Kinase; D007703:Peptidyl-Dipeptidase A; D000109:Acetylcholine