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Mechanistic Insights from Vascular and Cardiac Impairments in Rats Inhaling Diesel Exhaust Particles and Ozone
Citation:
KODAVANTI, U. P., R. Thomas, A. K. LUND, M. SCHLADWEILER, M. J. CAMPEN, J. H. Shannahan, A. D. LEDBETTER, A. Nyska, AND N. Parinandi. Mechanistic Insights from Vascular and Cardiac Impairments in Rats Inhaling Diesel Exhaust Particles and Ozone. Presented at 2010-NIEHS-EPA Symposium on Air Pollution and Cardiovascular Disease, Seattle, WA, June 21 - 22, 2010.
Impact/Purpose:
This Abstract examined the effect of ozone and diesel exhaust particles on vascular response, cardiac lipid oxidation, and lipid signaling in rats followmg episodic subchromc or acute exposures. The data show that vascular effects are likely mediated through oxidized lipid byproducts and endothelial signaling.
Description:
Although the causality has been established between air pollution and cardiovascular impairments, the molecular mechanisms are unknown. Moreover, cardiovascular effects of ozone have not been studied until recently. We hypothesize that vasculature and cardiac tissues are targets of subchronic effects of either ozone or diesel exhaust particles (DEP). And that ozone+DEP combined will be more toxic than individual pollutant alone. We also postulated that the nature of molecular effects on vasculature will be different from that of the cardiac tissue. We exposed male Wistar Kyoto rats (12-15 wk old), nose-only to air, ozone (0.5 ppm), re-suspended DEP from a 30 kW Deutz engine (2.0 mg/m\ or ozone+DEP, 5 hId for 1 dlwk for 16 wk. To determine if subchronic effects were not due to the final exposure to DEP or ozone, an acute study was performed. Rats were exposed to air, ozone (0.5 or 1.0 ppm), or DEP (2.0 mg/m ) for 5h/d x 2 d. We analyzed lung and systemic clinical biomarkers of cardiovascular injury. Biomarkers of oxidative stress and inflammation, vascular thrombosis, vasoconstriction and proteolytic changes were analyzed at mRNA level in three tissues "* in parallel (lung, heart and aorta>. Further, mRNA as well as protein levels of receptors which recognized circulating lipid oxidation byproducts (LOX-1), and protein oxidation byproducts (RAGE) were analyzed. Cardiac mitochondrial fatty acid composition was analyzed in the subchronic study. Modest pulmonary inflammation was evident in acute and subchronic ozone and/or DEP-exposed rats. Gene expressions for any of the biomarkers were not affected in the lung or in the heart by either ozone or DEP. However, marked upregulations were noted in the aorta for biomarkers of oxidative stress (HO-1), inflammation (MIP-2), thrombosis (TF, PAI-1, tPA, and vWf), vasoconstriction (ET-1, ET receptor A and B, eNOS) and proteolysis (MMP-2, MMP-3, MMP-9 and TIMP-2) in~6-wk study. An example of a change in t-PA is shown below. Aortic LOX-1 protein was increased by ozone and ozone+DEP (see above) with a trend of increase in mRNA. RAGE mRNA was slightly increased by ozone+DEP. Exposure to either ozone or DEP depleted cardiac mitochondrial phospholipid fatty acids. The combined effects of ozone+DEP were less pronounced than either pollutant alone. Acute exposures caused relatively mild changes in the aorta. These results suggest a potential role of membrane lipid oxidation and LOX-1-mediated signaling in vascular oxidative and inflammatory injury following subchronic, episodic ozone and DEP exposures. (Does not reflect US EPA policy). Supported in part by EPA NCBAlSEE Program and EPAIUNC #CT829471.