NOXA1-dependent NADPH oxidase regulates redox signaling and phenotype of vascular smooth muscle cell during atherogenesis

Aleksandr E. Vendrov; Arihiro Sumida; Chandrika Canugovi; Andrey Lozhkin; Takayuki Hayami; Nageswara R. Madamanchi; Marschall S. Runge

Redox Biology (Feb 2019)

NOXA1-dependent NADPH oxidase regulates redox signaling and phenotype of vascular smooth muscle cell during atherogenesis

Aleksandr E. Vendrov,
Arihiro Sumida,
Chandrika Canugovi,
Andrey Lozhkin,
Takayuki Hayami,
Nageswara R. Madamanchi,
Marschall S. Runge

Affiliations

Aleksandr E. Vendrov: Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Arihiro Sumida: Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Chandrika Canugovi: Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Andrey Lozhkin: Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Takayuki Hayami: Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Nageswara R. Madamanchi: Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Marschall S. Runge: Correspondence to: Department of Internal Medicine, University of Michigan, 7324 Medical Sciences Building I, 1301 Catherine St., Ann Arbor, MI 48109, USA.; Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA

Journal volume & issue: Vol. 21

Abstract

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Increased reactive oxygen species (ROS) production and inflammation are key factors in the pathogenesis of atherosclerosis. We previously reported that NOX activator 1 (NOXA1) is the critical functional homolog of p67phox for NADPH oxidase activation in mouse vascular smooth muscle cells (VSMC). Here we investigated the effects of systemic and SMC-specific deletion of Noxa1 on VSMC phenotype during atherogenesis in mice.Neointimal hyperplasia following endovascular injury was lower in Noxa1-deficient mice versus the wild-type following endovascular injury. Noxa1 deletion in Apoe-/- or Ldlr-/- mice fed a Western diet showed 50% reduction in vascular ROS and 30% reduction in aortic atherosclerotic lesion area and aortic sinus lesion volume (P < 0.01). SMC-specific deletion of Noxa1 in Apoe-/- mice (Noxa1SMC-/-/Apoe-/-) similarly decreased vascular ROS levels and atherosclerotic lesion size. TNFα-induced ROS generation, proliferation and migration were significantly attenuated in Noxa1-deficient versus wild-type VSMC. Immunofluorescence analysis of atherosclerotic lesions showed a significant decrease in cells positive for CD68 and myosin11 (22% versus 9%) and Mac3 and α-actin (17% versus 5%) in the Noxa1SMC-/-/Apoe-/- versus Apoe-/- mice. The expression of transcription factor KLF4, a modulator of VSMC phenotype, and its downstream targets – VCAM1, CCL2, and MMP2 – were significantly reduced in the lesions of Noxa1SMC-/-/Apoe-/- versus Apoe-/- mice as well as in oxidized phospholipids treated Noxa1SMC-/- versus wild-type VSMC.Our data support an important role for NOXA1-dependent NADPH oxidase activity in VSMC plasticity during restenosis and atherosclerosis, augmenting VSMC proliferation and migration and KLF4-mediated transition to macrophage-like cells, plaque inflammation, and expansion. Keywords: Oxidative stress, NOXA1, Smooth muscle cells, KLF4, Macrophage-like cells, Atherosclerosis

Published in Redox Biology

ISSN: 2213-2317 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.journals.elsevier.com/redox-biology/

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