p47phox is required for atherosclerotic lesion progression in ApoE(-/-) mice

NADPH oxidase is upregulated in smooth muscle cells (SMCs) in response to g rowth factor stimulation, concomitant with increased reactive oxygen specie s (ROS) production. We investigated the role of ROS production by NADPH oxi dase in SMC responses to growth factors and in atherosclerotic lesion forma tion in ApoE(-/-) mice. SMCs from wild-type, p47phox(-/-), and gp91phox(-/- ) mice differed markedly with respect to growth factor responsiveness and R OS 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 fr om that of wild-type SMCs. The relevance of these in vitro observations was tested by measuring atherosclerotic lesion formation in genetically modifi ed (wild-type, p47phox(-/-), ApoE-/-, and ApoE(-/-)/p47phox(-/-)) mice. Apo E(-/-)/p47phox(-/-) mice had less total lesion area than ApoE(-/-) mice, re gardless of whether mice were fed standard chow or a high-fat diet. Togethe r, these studies provide convincing support for the hypothesis that superox ide generation in general, and NADPH oxidase in particular, have a requisit e role in atherosclerotic lesion formation, and they provide a rationale fo r further studies to dissect the contributions of ROS to vascular lesion fo rmation.