TY - JOUR
T1 - p47phox is required for atherosclerotic lesion progression in ApoE-/- mice
AU - Barry-Lane, Patricia A.
AU - Patterson, Cam
AU - Van Der Merwe, Marié
AU - Hu, Zhaoyong
AU - Holland, Stephen M.
AU - Yeh, Edward T.H.
AU - Runge, Marschall S.
PY - 2001
Y1 - 2001
N2 - NADPH oxidase is upregulated in smooth muscle cells (SMCs) in response to growth factor stimulation, concomitant with increased reactive oxygen species (ROS) production. We investigated the role of ROS production by NADPH oxidase in SMC responses to growth factors and in atherosclerotic lesion formation in ApoE-/- mice. SMCs from wild-type, p47phox-/-, and gp91phox-/- mice differed markedly with respect to growth factor responsiveness and ROS generation, p47phox-/- SMCs had diminished superoxide production and a decreased proliferative response to growth factors compared with wild-type cells, whereas the response of gp91phox-/- SMCs was indistinguishable from that of wild-type SMCs. The relevance of these in vitro observations was tested by measuring atherosclerotic lesion formation in genetically modified (wild-type, p47phox-/-, ApoE-/-, and ApoE-/-/p47phox-/-) mice. ApoE-/-/p47phox-/- mice had less total lesion area than ApoE-/- mice, regardless of whether mice were fed standard chow or a high-fat diet. Together, these studies provide convincing support for the hypothesis that superoxide generation in general, and NADPH oxidase in particular, have a requisite role in atherosclerotic lesion formation, and they provide a rationale for further studies to dissect the contributions of ROS to vascular lesion formation.
AB - NADPH oxidase is upregulated in smooth muscle cells (SMCs) in response to growth factor stimulation, concomitant with increased reactive oxygen species (ROS) production. We investigated the role of ROS production by NADPH oxidase in SMC responses to growth factors and in atherosclerotic lesion formation in ApoE-/- mice. SMCs from wild-type, p47phox-/-, and gp91phox-/- mice differed markedly with respect to growth factor responsiveness and ROS generation, p47phox-/- SMCs had diminished superoxide production and a decreased proliferative response to growth factors compared with wild-type cells, whereas the response of gp91phox-/- SMCs was indistinguishable from that of wild-type SMCs. The relevance of these in vitro observations was tested by measuring atherosclerotic lesion formation in genetically modified (wild-type, p47phox-/-, ApoE-/-, and ApoE-/-/p47phox-/-) mice. ApoE-/-/p47phox-/- mice had less total lesion area than ApoE-/- mice, regardless of whether mice were fed standard chow or a high-fat diet. Together, these studies provide convincing support for the hypothesis that superoxide generation in general, and NADPH oxidase in particular, have a requisite role in atherosclerotic lesion formation, and they provide a rationale for further studies to dissect the contributions of ROS to vascular lesion formation.
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U2 - 10.1172/JCI200111927
DO - 10.1172/JCI200111927
M3 - Article
C2 - 11714743
AN - SCOPUS:0035179016
SN - 0021-9738
VL - 108
SP - 1513
EP - 1522
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 10
ER -