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NOXA1-dependent NADPH oxidase regulates redox signaling and phenotype of
vascular smooth muscle cell during atherogenesis.
Authors Vendrov AE, Sumida A, Canugovi C, Lozhkin A, Hayami T, Madamanchi NR, Runge MS
Submitted By Submitted Externally on 4/15/2019
Status Published
Journal Redox biology
Year 2019
Date Published 2/1/2019
Volume : Pages 21 : 101063
PubMed Reference 30576919
Abstract 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?SMC-specific deletion of Noxa1 in Apoe-/- mice (Noxa1SMC-/-/Apoe-/-) similarly
decreased vascular ROS levels and atherosclerotic lesion size. TNFa-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 a-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.


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