NADPH Oxidase Deficiency Exacerbates Angiotensin II–Induced Abdominal Aortic Aneurysms in Mice

Abstract

Objective— Although nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) is reportedly essential for phagocyte host defenses, it has been found to aggravate atherosclerosis in apolipoprotein E ( Apoe )-null mice through excess production of superoxide. We therefore assessed the role of NOX2 in an experimental model of abdominal aortic aneurysm (AAA) and assessed the mechanism of NOX2 action in AAA. Approach and Results— AAA was induced in low-density lipoprotein receptor-null ( Ldlr –/– ) mice by infusing angiotensin II. Nox2 expression was elevated in the abdominal aortae of these mice during infusion of angiotensin II, with enhanced Nox2 expression mainly because of the recruitment of NOX2-enriched macrophages into AAA lesions. Unexpectedly, systemic Nox2 deficiency promoted AAA development but reduced the level of reactive oxygen species in AAA lesions. Nox2 deficiency stimulated macrophage conversion toward the M1 subset, enhancing expression of interleukin (IL)-1β and matrix metalloproteinase-9/12 mRNA. Administration of neutralizing antibody against IL-1β abolished AAA development in Nox2 -deficient mice. Bone marrow transplantation experiments revealed that AAA aggravation by Nox2 deficiency is because of bone marrow–derived cells. Isolated bone marrow–derived macrophages from Nox2 -null mice could not generate reactive oxygen species. In contrast, IL-1β expression in peritoneal and bone marrow–derived macrophages, but not in peritoneal neutrophils, was substantially enhanced by Nox2 deficiency. Pharmacological inhibition of Janus kinase/signal transducers and activators of transcription signaling inhibited excess IL-1β expression in Nox2 -deficient macrophages, whereas matrix metalloproteinase-9 secretion was constitutively stimulated via nuclear factor-κB signals. Conclusions— Nox2 deficiency enhances macrophage secretion of IL-1β and matrix metalloproteinase-9, disrupting tissue-remodeling functions in AAA lesions. These actions are unfavorable if NOX2 is to serve as a molecular target for AAA.

Selective inactivation of NADPH oxidase 2 causes regression of vascularization and the size and stability of atherosclerotic plaques

“…Our findings are ostensibly in contrast with a recent experimental study in Nox2-deficient mice in which MMP-9 activity in the adventitia, but not media, was upregulated in aggravated abdominal aortic aneurysm (AAA) lesions, suggesting that a deficiency in Nox2 markedly perturbs proinflammatory cascades in macrophages present in AAA [43]. Thus, it is important to carefully monitor inflammatory phenotype when Nox2 intervention is conducted and this issue will also need to be investigated in humans.…”

Mesenchymal Stem Cells Attenuate NADPH Oxidase-Dependent High Mobility Group Box 1 Production and Inhibit Abdominal Aortic Aneurysms

“…demonstrated that p47phox was mainly expressed in macrophages and upregulated during cerebral aneurysm formation 26 . On the other hand, a recent study by Kigawa et al showed that NADPH oxidase deficiency can exacerbate angiotensin-II induced AAA formation in mice 27 . This unexpected occurrence of hyperinflammation by Nox2 deficiency is contrary to our findings where elastase-perfused Nox2 −/y mice were significantly protected from AAA.…”

Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing

“…The isolation of BMMs was performed as described in our previous study (33). Briefly, murine BM cells were collected by flushing femoral BM with culture medium; subsequently, the cells were incu- technology Inc.).…”

“…BM transplantation. BM transplantation was conducted as previously described (33 were sacrificed, and aortic sinus and whole blood with EDTA were collected. Erythrocytes in the whole blood samples were lysed with BD Pharm Lyse (BD Biosciences); then the samples were analyzed by using BD FACSVerse (BD Biosciences) to evaluate the uptake of fluorescence beads in monocyte population.…”