Abstract 1207: Ambient Ultrafine Particulate Matter Enhances Atherosclerosis in apoE Null Animals
Epidemiological studies suggest that exposure to ambient particulate matter (PM) constitutes a risk factor for atherosclerosis. Exposure to fine PM (particles with aerodynamic diameter < 2.5 μm, PM2.5) has been shown to promote atherogenesis in apoE null mice. We hypothesized that PM synergizes with known proatherogenic stimuli and mediators in their ability to elicit oxidative stress and promote atherosclerosis, and that most of the pro-inflammatory potential resides in the ultrafine particles (aerodynamic diameter < 0.1 μm, UFP) that are highly enriched for redox cycling PM chemicals. To test our hypothesis:
In-vivo: we evaluated the development of atherosclerotic lesions in 7-week-old apoE null male mice exposed to concentrated ambient PM (CAPS). Mice were assigned to four different groups: non-exposed (NE), filtered air (FA), concentrated PM2.5 (FP) and concentrated UFP. NE mice were kept at the UCLA vivarium. FA, FP and UFP mice were housed in a mobile animal laboratory located in downtown Los Angeles, and exposed to FA or CAPS for a combined total of 75 hours over a period of 40 days. Atherosclerosis was assessed by histological examination of the ascending aorta and expressed as average lesional area (μm2/section). Concentrated (17x) UFP animals developed significantly greater atherosclerotic lesions (33011 +/− 3741, n=15) as compared with NE (17261 +/− 1659, n= 17, p = 0.0002) or FA mice (21362 +/− 2864, n= 15, p = 0.02), and a similar trend in comparison to mice exposed to concentrated (13x) FP (26361 +/−2275, n= 16, p=0.06). Increased oxidative stress was documented systemically by the significant up-regulation of the p45-NFE2 related factor-2 (Nrf2) and its efferent phase-2 response genes in the liver and aorta.
In vitro: we employed a human microvascular endothelial cell line and noted by microarray technology that diesel exhaust particles (5 μg/ml), that contribute to UFP, synergized with an oxidized LDL proatherogenic mediator, palmitoylarachidonyl-phosphatidyl choline (10, 20 and 40 μg/ml), in the up-regulation (>1.5X) of a large number of genes (n=626). In conclusion, exposure to pro-oxidative UFP exacerbates atherosclerosis in apoE null mice and appears to act synergistically with oxidized LDL components in the vascular wall.