Abstract
Of the multiple sources of reactive oxygen species (ROS) in the blood vessel, NADPH oxidases are the primary source. Whereas several studies have implicated NADPH oxidases in the initiation of atherosclerosis, their roles in disease progression are incompletely understood. Our objective was to determine the potential clinical relevance of inhibiting NADPH oxidase in established atherosclerosis. Using a hypercholesteremic murine model of atherosclerosis (ApoE−/−/LDLR−/− (AS) mice on normal chow diet), we first established a time-dependent relationship between superoxide levels and lesion size in AS mice. Next, we identified NADPH oxidase as the primary source of ROS in atherosclerotic lesions. Treatment of aortic segments from AS mice with apocynin, which interferes with NADPH oxidase activation in part by preventing translocation of the subunit p47phox, significantly reduced superoxide levels. Moreover, addition of apocynin to the drinking water of AS mice produced a decrease in lesion size as compared to untreated AS mice, with the effect most pronounced in the thoracoabdominal aorta but absent from the aortic arch. Granulocyte function in AS+apocynin mice was suppressed, confirming efficacy of apocynin treatment. We conclude that apocynin attenuates the progression of atherosclerosis in hypercholesterolemic mice, potentially by its ability to inhibit generation of superoxide by NADPH oxidase.
Highlights
The mechanisms of atherosclerosis are complex, involving initial events of transendothelial migration of inflammatory cells into the vascular wall and formation of fatty streaks and later events that include vascular cell activation and more complex lesion development
Of the seven NADPH oxidase catalytic (Nox) isoforms, only Nox1, Nox2, Nox4 and Nox5 are expressed in the blood vessel, and they differ in their cell-specific expression, mode of activation, subunit requirements, and function [1]
We examined whether treatment with apocynin after the development of atherosclerosis in mice either blocked progression or induced regression by treating mice with apocynin beginning at
Summary
The mechanisms of atherosclerosis are complex, involving initial events of transendothelial migration of inflammatory cells into the vascular wall and formation of fatty streaks and later events that include vascular cell activation and more complex lesion development. Several studies have implicated NADPH oxidase in the development and early progression of atherosclerosis. A limitation of these studies in genetically modified mice is that the mechanisms of the initiation of disease may be distinct from those involved in disease progression. As such, this limits the clinical relevance of the suggested benefit of NADPH oxidase deficiency. Treatment with the NADPH oxidase inhibitor apocynin beginning at 17 weeks of age and continued for an additional 17 weeks reduced vascular ROS and attenuated lesion progression
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