School of Medicine
Area of interest
Oxidative stress has long been thought to contribute to atherosclerosis in humans. This is largely based on evidence that oxidative modifications of lipoproteins is critical for atherosclerotic lesion formation. However, it is likely that oxidative events other than altered lipid metabolism also play an important role in the pathogenesis of atherosclerosis. We have recently shown that reactive oxygen species in general and NAD(P)H oxidase in particular are required for atherogenic phenotype using ApoE and p47phox double knockout mice.1 However, the respective roles of circulating macrophages and the resident smooth muscle cells of vascular wall in atherogenesis have not been investigated. Current work in the laboratory is aimed at addressing this issue using bone marrow transplantation technique. We are also employing microarray methodology using wild-type and p47phox knockout mouse vascular smooth muscle cells (SMC) to gain a global perspective of NAD(P)H oxidase- and thrombin-dependent gene transcription.
In an another approach, we have investigated the effect of increased oxidative stress, in particular increased superoxide production in mitochondria, on atherosclerotic lesion formation.2 Our results showed accelerated atherosclerosis at arterial branch points and increased mitochondrial DNA damage in ApoE knockout and superoxide dismutase 2 (SOD2) knockdown mice compared to ApoE knockout mice. In continuation of this work, we are investigating the role of subcellular ROS localization on SMC phenotype and activation of mitogenic signaling events using mouse SMC deficient in SOD. Both SOD1+/- and SOD2+/- SMC exhibit increased cell proliferation under basal conditions and enhanced 3H-thymidine and 3H-leucine incorporation, increased ROS production under both basal and thrombin-stimulated conditions. Despite these similarities, the two cell types differ in their intracellular signaling pathways. ERK1/2 and p38 MAP kinases are preferentially activated in SOD1+/- SMC, and whereas the JAK/STAT pathway is activated in SOD2+/- SMC. These results suggest: 1) that SOD1 and SOD2 regulate SMC growth utilizing distinct signaling systems and that dysregulation of these enzymes under pathophysiological conditions could contribute to altered growth independently; and 2) that a key component in the cellular response to ROS is the type and cellular location of SOD.