NOX1 deficiency protects from aortic dissection in response to angiotensin II.
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.
Gavazzi
Gaetan
G
Department of Geriatrics, University Hospital of Grenoble, Grenoble, France.
Deffert
Christine
C
Trocme
Candice
C
Schäppi
Michela
M
Herrmann
François R
FR
Krause
Karl-Heinz
KH
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
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