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NOX1 deficiency protects from aortic dissection in response to angiotensin II

Deffert, Christine
Trocme, Candice
Schappi, Michela
Published in Hypertension. 2007, vol. 50, no. 1, p. 189-196
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.
Keywords Aneurysm, Dissecting/ chemically induced/ prevention & controlAngiotensin IIAnimalsAorta, Thoracic/metabolismAortic Aneurysm/ chemically induced/ prevention & controlBlood Pressure/drug effectsDisease SusceptibilityGene Expression Regulation/drug effectsHypertension/chemically inducedMaleMatrix Metalloproteinase 2/metabolismMatrix Metalloproteinase 9/metabolismMiceMice, Inbred C57BLMice, KnockoutNADPH Oxidase/ deficiencyNorepinephrine/pharmacologyRNA, Messenger/metabolismTissue Inhibitor of Metalloproteinase-1/genetics/metabolismVasoconstrictor Agents
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Other version: http://hyper.ahajournals.org/cgi/reprint/50/1/189.pdf
PMID: 17502491
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