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Abstract 379: Modulation of Inflammatory Signaling by PPARα and PPARγ in Acrolein-Treated gp91phox Knockout Mice

Acrolein, a copious environmental pollutant plays a role in development of inflammation in vasculature. Oxidative stress & inflammation are important in acrolein-induced toxicity. Peroxisome Proliferator Activated receptor alpha and gamma (PPARα and PPARγ) and their ability to influence oxidative stress (OS) has been the focus of inflammatory signaling. NAD(P)H oxidase is a source of free radical generation. This study investigated the influence of PPARα and γ ligands (clofibrate & GW1929) in attenuating oxidative stress in acrolein-induced insult. gp91phox knockout (KO) mice and age/weight matched wild type (WT) were treated with acrolein (0.5 μg/kg; i.p.; 7 days) with/without clofibrate (Clof: 250 mg/kg; i.p; 10 days) or GW1929 (5 mg/kg, gavage, 10 days). KO mice (1.44±0.14 pg/μg prt) had higher (97%) 8-Isoprostane in response to acrolein than WT (2.19±0.11 pg/μg prt). Clof had no effect on 8-Isoprostane but GW1929 reduced it in both WT and KO mice by 35% and 43% (p<0.05) respectively. There was a significant reduction in Total Antioxidant Status (TAS) which was more prominent in WT (69%) than KO (53%). Clof and GW1929 improved TAS in WT (21% and 19%). Xanthine Oxidase (XO) enzyme activity was higher in KO (0.53±0.05) than WT (0.35+0.02). Acrolein and clof increased XO activity in WT while GW1929 had no effect. Acrolein increased cycloxygenase (COX) in WT (4.58±0.3) and remained at basal level in KO. Clof and GW1929 reduced COX in WT (54% and 48% respectively). Clof reduced Cox only in KO mice (31%). NFκB activity was twice in acrolein treated WT and remained unchanged in KO. Both GW1929 and clof blunted this increase. Acrolein increased CD36 activity, an inflammatory marker, in KO (56%). Clof attenuated this increase in KO but increased it in acrolein treated WT. GW1929 blunted CD36 increase in KO mice but did not affect WT. These results suggest that in absence of a functioning NAD(P)H oxidase other oxygenase contributes in acrolein-induced oxidative stress and PPARα ligand, clofibrate, is beneficial via attenuating inflammatory signaling of NFκB and COX. We also suggest that beneficial effect of PPARγ ligand involves inhibition of NAD(P)H oxidase as in absence of NAD(P)H this effects are minimal.