TY - JOUR
T1 - Induction of angiotensin-converting enzyme and activation of the renin-angiotensin system contribute to 20-hydroxyeicosatetraenoic acid-mediated endothelial dysfunction
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
PY - 2012/8
Y1 - 2012/8
N2 - 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.
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.
KW - angiotensin II
KW - eicosanoids
KW - hypertension
KW - nitric oxide
KW - superoxide
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U2 - 10.1161/ATVBAHA.112.248344
DO - 10.1161/ATVBAHA.112.248344
M3 - Article
C2 - 22723444
AN - SCOPUS:84864280330
SN - 1079-5642
VL - 32
SP - 1917
EP - 1924
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 8
ER -