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SUSCEPTIBILITY TO OZONE-INDUCED INJURY AND ANTIOXIDANT COMPENSATION IN RAT MODELS OF CARDIOVASCULAR DISEASE
Citation:
KODAVANTI, U. P., M. SCHLADWEILER, A. D. LEDBETTER, R. GOTTIPOLU, G. WALLENBORN, R. H. JASKOT, R. THOMAS, J. E. RICHARDS, K. M. CRISSMAN, G. E. HATCH, D. MALARKEY, R. MARONPOT, W. O. WARD, S. D. HESTER, G. KISSLING, AND A. NYSKA. SUSCEPTIBILITY TO OZONE-INDUCED INJURY AND ANTIOXIDANT COMPENSATION IN RAT MODELS OF CARDIOVASCULAR DISEASE. Presented at Meeting of the Society for Free Radical Biology and Medicine, Denver, CO, November 15 - 19, 2006.
Description:
Increased oxidative stress and compromised antioxidant status are common pathologic factors of cardiovascular diseases (CVD). It is hypothesized that individuals with chronic CVD are more susceptible to environmental exposures due to underlying oxidative stress. To determine the role of oxidative stress in susceptibility to oxidant-induced injury, we asked the following questions: 1) Are rat strains that demonstrate various forms of genetic/polygenic CVD deficient in antioxidant reserve? 2) Does their antioxidant status predict susceptibility to acute ozone-induced oxidative injury? 3) Are there links between susceptibilities to injury from ozone, antioxidants and gene regulation? To answer these questions, eight strains of rats, healthy or with CVD known to have increased oxidative stress were selected. Male 12-15 wk old Sprague Dawley SD), Wistar (WIS), Wistar Kyoto (WKY), Spontaneously Hypertensive (SH), Stroke-prone SH (SHSP), Heart Failure Hypertensive (SHHF), Diabetic with CVD (JCR), and Fawn Hooded Hypertensive (FHH) rats were exposed nose-only to ozone (0.0, 0.25, 0.5 or 1.0 ppm for 4 h). Lung, heart, and lung lining fluid antioxidants (glutathione and ascorbate), cardiac pathology, lung injury/inflammation, and gene expression were analyzed. Rats with CVD had lower lutathione in the heart but not in the lung relative to healthy ones, suggesting that the organ specific antioxidant deficiency likely occurs through epigenetic mechanisms. Ozone caused dose-dependent injury and inflammation to a variable degree in all rat strains. Lung vascular leakage was greater in SHSP, SHHF, SH, WIS, and neutrophilic inflammation was greater in FHH, WIS, SHSP and WKY rats suggesting no clear relationship between ozone susceptibility and CVD. Most rat strains responded to ozone exposure by depletion in ascorbate in lung lining fluid, consistent with ascorbate being a first line of antioxidant defense. Rats with CVD or lower antioxidant levels did not necessarily demonstrate greater ascorbate and glutathione depletion or injury; however, ozone-induced induction of HO-1 mRNA was inversely related to ascorbate in lung lining fluid. Principle component analysis of expression data separately clustered groups of genes dependent upon specific disease and ozone exposure status. Our results provide insight into the relationships among antioxidant levels, underlying CVD and ozone-induced inflammatory response which may not be generalized for all rat strains or disease conditions. (Does not reflect USEPA policy).