Published Online
on May 14, 2007

A more recent version of this article appeared on July 1, 2007

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Submitted on February 21, 2007
Revised on March 19, 2007

NOX1 Deficiency Protects From Aortic Dissection in Response to Angiotensin II

Gaetan Gavazzi; Christine Deffert; Candice Trocme; Michela Schäppi; François R. Herrmann; and Karl-Heinz Krause^*

From the Department of Geriatrics (G.G.) and Groupe de Recherche et d’Etude du Processus Inflammatoire Techniques de I’Ingénierie Médicale et de la Complexité-Imag Unité Mixtede Recherche-Centre National de la Recherche Scientifique 5525 (G.G., C.T.), University Hospital of Grenoble, Grenoble, France; and the Departments of Pathology, Immunology, and Clinical Pathology (C.D., M.S., K-H.K.), Pediatrics (C.D.), and Rehabilitation and Geriatrics (F.R.H.), Geneva Medical Faculty, Geneva, Switzerland.

^* To whom correspondence should be addressed. E-mail: karl-heinz.krause{at}medecine.unige.ch.

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.

Key words: NOX1 • nicotinamide-adenine dinucleotide phosphate oxidase • blood pressure • aortic dissection • angiotensin II

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