title: Knockdown of angiopoietin like-2 protects against angiotensin II-induced cerebral endothelial dysfunction in mice.
abstract: Angiopoietin like-2 (angptl2) is a circulating pro-inflammatory and pro-oxidative protein, but its role in regulating cerebral endothelial function remains unknown. We hypothesized that in mice knockdown (KD) of angptl2, cerebral endothelial function would be protected against ANG II-induced damage. Subcutaneous infusion of ANG II (200 ng·kg(-1)·min(-1), n = 15) or saline (n = 15) was performed in 20-wk-old angptl2 KD mice and wild-type (WT) littermates for 14 days. In saline-treated KD and WT mice, the amplitude and the sensitivity of ACh-induced dilations of isolated cerebral arteries were similar. However, while endothelial nitric oxide (NO) synthase (eNOS)-derived O2 (-)/H2O2 contributed to dilation in WT mice, eNOS-derived NO (P < 0.05) was involved in KD mice. ANG II induced cerebral endothelial dysfunction only in WT mice (P < 0.05), which was reversed (P < 0.05) by either N-acetyl-l-cysteine, apocynin, gp91ds-tat, or indomethacin, suggesting the contribution of reactive oxygen species from Nox2 and Cox-derived contractile factors. In KD mice treated with ANG II, endothelial function was preserved, likely via Nox-derived H2O2, sensitive to apocynin and PEG-catalase (P < 0.05), but not to gp91ds-tat. In the aorta, relaxation similarly and essentially depended on NO; endothelial function was maintained after ANG II infusion in all groups, but apocynin significantly reduced aortic relaxation in KD mice (P < 0.05). Protein expression levels of Nox1/2 in cerebral arteries were similar among all groups, but that of Nox4 was greater (P < 0.05) in saline-treated KD mice. In conclusion, knockdown of angptl2 may be protective against ANG II-induced cerebral endothelial dysfunction; it favors the production of NO, likely increasing endothelial cell resistance to stress, and permits the expression of an alternative vasodilatory Nox pathway.
authors.affiliation: Montreal Heart Institute, Research Center, Montreal, Quebec, Canada; Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; and.
authors.forename: Carol
authors.initials: C
authors.lastname: Yu
authors.affiliation: Montreal Heart Institute, Research Center, Montreal, Quebec, Canada;
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Luo
authors.affiliation: Montreal Heart Institute, Research Center, Montreal, Quebec, Canada;
authors.forename: Natacha
authors.initials: N
authors.lastname: Duquette
authors.affiliation: Montreal Heart Institute, Research Center, Montreal, Quebec, Canada;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Thorin-Trescases
authors.affiliation: Montreal Heart Institute, Research Center, Montreal, Quebec, Canada; Department of Surgery, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada eric.thorin@umontreal.ca.
authors.forename: Eric
authors.initials: E
authors.lastname: Thorin
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002536:Cerebral Arteries / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D017353:Gene Deletion; D006023:Glycoproteins / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D014661:Vasoconstriction
chemical_list: D000098:Acetophenones; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C485793:Angptl2 protein, mouse; D006023:Glycoproteins; C473031:gp91ds-tat protein, chimeric; D000804:Angiotensin II; D009569:Nitric Oxide; C056165:acetovanillone; D006861:Hydrogen Peroxide; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin
keywords: NADPH oxidases; angiopoietin like-2; cerebral arteries; endothelium; nitric oxide