title: NOX1 deficiency protects from aortic dissection in response to angiotensin II.
abstract: Oxidative stress leads to vascular damage and participates in the pathomechanisms of aortic dissection and aneurysm formation. Here we study aortic dissection in mice deficient in the superoxide-generating reduced nicotinamide-adenine dinucleotide phosphate oxidase NOX1. Seven days of treatment with the hypertensive agent angiotensin II (3 mg/kg per day) led to aortic dissection in 23% of wild-type C57BL/6J mice but in only 4% of NOX1-deficient mice (P=0.05). In contrast, treatment of wild-type C57BL/6J mice with the hypertensive agent norepinephrine (12 mg/kg per day), did not lead to aortic dissection or sudden death, suggesting that hypertension is not sufficient to cause aortic dissection. Interestingly, norepinephrine-dependent blood pressure elevations were conserved in NOX1-deficient mice, demonstrating that, different from angiotensin II, it acts through NOX1-independent hypertensive mechanisms. The resistance of NOX1-deficient mice to angiotensin II-induced aortic dissection suggests a role for NOX1-dependent alterations of the vascular wall. We, therefore, studied gene expression and protease/inhibitor equilibrium. cDNA array analysis demonstrated differential effects of angiotensin II on gene expression in wild-type and NOX1-deficient mice. Tissue inhibitor of metalloproteinase 1 was increased both on the mRNA and the protein level in aortas from NOX1-deficient mice. Thus, our results demonstrate that NOX1 is involved in the mechanisms of angiotensin II-dependent aortic dissection. As one underlying mechanism, we have identified NOX1-dependent suppression of tissue inhibitor of metalloproteinase 1 expression, which could lead to tissue damage through an altered protease/inhibitor balance.
authors.affiliation: Department of Geriatrics, University Hospital of Grenoble, Grenoble, France.
authors.forename: Gaetan
authors.initials: G
authors.lastname: Gavazzi
authors.forename: Christine
authors.initials: C
authors.lastname: Deffert
authors.forename: Candice
authors.initials: C
authors.lastname: Trocme
authors.forename: Michela
authors.initials: M
authors.lastname: Schäppi
authors.forename: François R
authors.initials: FR
authors.lastname: Herrmann
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Krause
mesh_terms: D000784:Aortic Dissection / Q000139:chemically induced* / Q000517:prevention & control*; D000804:Angiotensin II; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D001014:Aortic Aneurysm / Q000139:chemically induced* / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D004198:Disease Susceptibility; D005786:Gene Expression Regulation / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000172:deficiency*; D009638:Norepinephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014662:Vasoconstrictor Agents
chemical_list: D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D009638:Norepinephrine