Abstract 3961: Macrophage Catalase Overexpression Inhibits Atherosclerosis and Vascular Inflammation
Previous studies have supported a linkage between hydrogen peroxide (H2O2), intracellular signaling cascades, vascular inflammation, and atherosclerosis. However, the precise role and relevance of macrophage-derived H2O2 in these processes has not been determined. To address this question, we developed transgenic mice on an apoE−/− background with overexpression of catalase in macrophages driven by the lysozyme promoter (Tgcat-mac). Overexpression of the human catalase gene in macrophages was confirmed by immunostaining, and increased enzymatic activity using an Amplex Red-based fluorometric assay on cells obtained from a peritoneal lavage. Tgcat-mac mice were normotensive at baseline and exhibited a hypertensive response to 0.75 mg/kg/day of angiotensin II that did not differ from that of controls. Atherosclerotic lesion surface area was analyzed using en-face preparations of the descending aorta. Tgcat-mac mice were almost completely protected against atherosclerosis that occurred in response to treatment with angiotensin II and/or a high fat atherogenic diet (81.78 ± 7.2 versus 9.63 ± 2 percent lesion surface area in the group receiving the combination treatment; P<0.05). This protective effect was also present in cross sections of the proximal ascending aorta (211220 ± 33150 versus 73214 ± 11889 μm2 cross-sectional area in the group receiving the combination treatment; P<0.05). In addition, while abdominal aortic aneurysm (AAA) formation occurred in 33 % of the angiotensin II-treated ApoE−/− control mice, Tgcat-mac exhibited a complete inhibition of AAA formation. Plasminogen activator inhibitor-1 (PAI-1), monocyte chemoattractant protein-1 (MCP-1) and osteopontin (OPN) expression were reduced in Tgcat-mac macrophages demonstrating an anti-inflammatory effect of catalase overexpression. These results indicate that H2O2 in general and macrophage-derived H2O2 specifically, plays a critical role in the pathogenesis of atherosclerosis and AAA via regulation of a pro-inflammatory state.