NOX1 Deficiency Protects From Aortic Dissection in Response to Angiotensin II

Abstract

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 (Pϭ0.05). 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 Ⅲ nicotinamide-adenine dinucleotide phosphate oxidase Ⅲ blood pressure Ⅲ aortic dissection Ⅲ angiotensin II A ortic dissections and formation of aneurysms are serious and frequent medical conditions that are the consequence of damage to the vascular wall. Animals model play a key role in understanding their pathomechanisms. 1 Angiotensin II perfusion in mice has become a particularly valuable model for this pathological process. 2-5 Angiotensin II-induced vascular alterations include the following: (1) sustained blood pressure elevations; (2) increase in the thickness of the aortic media through mechanisms including smooth muscle hyperplasia, smooth muscle proliferation, and accumulation of extracellular matrix (ECM) proteins; (3) markers of inflammation, including oxidative damage to the vascular tissue, infiltration of monocytes/macrophages, and activation of matrix metalloproteinases; and (4) formation of aortic dissection and aneurysms. 1,4 Angiotensin II-dependent signal transduction is complex and involves Ն2 different receptors and the activation of multiple intracellular signaling pathways. 6,7 There is now increasing evidence that reactive oxygen species (ROS) are an important part of angiotensin II-dependent signal transduction 8 -12 involved in the pathogenesis of aortic aneurysms...

Activation of Src-ATF1 pathway is involved in upregulation of Nox1, a catalytic subunit of NADPH oxidase, by aldosterone

“…Compared with the unstimulated control, much stronger DHE stain- A B tone when following Ang II perfusion [29]. Further, Nox1 overexpression in a transgenic mice aggravated Ang II-induced hypertension and VSMCs hypertrophy [30].…”

Reactive Oxygen Species in Inflammation and Tissue Injury

“…In addition, NOX1-deficient mice were less susceptible to Ang II-induced aortic dissection and aneurysm formation (131). NOX1 was also important in angiogenesis and tumor formation.…”

Angiotensin II–Dependent Superoxide

“…Seven days of Ang II infusion induced aortic dissection in 23% of wild-type mice but only 4% of Nox1-deficient mice. 21 This study was particularly interesting because norepinephrine failed to generate aortic dissection, confirming the selective role of Ang II on NADPH oxidase.…”