Abstract 19334: Exposure to Diesel Exhaust Emissions Markedly Induce Systemic Lipid Peroxidation and the Development of Dysfunctional Prooxidative and Proinflammatory HDL

Abstract

Rationale: Exposure to ambient particulate matter is associated with increased cardiovascular ischemic events and enhanced atherosclerosis, likely due in part to the promotion of systemic pro-oxidant and pro-inflammatory effects.

Objective: The purpose of this study was to test our hypothesis that air pollutants may induce oxidative modifications of plasma lipoproteins resulting in alteration of the anti-oxidant and anti-inflammatory properties of high-density lipoproteins (HDL).

Methods and Results: We exposed ApoE-/- and C57BL/6 wild-type male mice to diesel exhaust (DE) emissions at 200-300 µg PM2.5/m3 for two weeks, filtered air (FA) for two weeks or DE for two weeks, followed by FA for one week (DE+FA). HDL anti-oxidant capacity was assessed by a DCF-based cell fluorescence assay that evaluate the ability of HDL to inhibit LDL oxidation, determined by the level of fluorescence intensity. In the ApoE-/- background, DE and DE+FA mice significantly impaired the HDL anti-oxidant capacity in comparison with FA mice (p<0.001), as judged by almost a doubling in the level of DCF fluorescence and by a promotion rather than inhibition of oxidation. Decreased HDL anti-oxidant properties was accompanied by reduced anti-inflammatory capacity, as determined by a monocyte chemotaxis assay. The HDL anti-oxidant dysfunction correlated with decreased paraoxonase enzymatic activity, increased levels of plasma 8-isoprostanes, 12-HETE, and 13-HODE as well as liver malondialdehyde and 5-HETE levels (p< 0.05), with subsequent up-regulation of hepatic anti-oxidant genes, activation of unfolded protein response and the 5-lipoxygenase pathway. Moreover, while DE led to enhanced lipid peroxidation in the bronchoalveolar lavage fluid of both ApoE-/- and C57BL/6J mice, there were no effects of DE exposure on systemic lipid peroxidation or HDL functionality in the latter.

Conclusions: DE emissions induced systemic pro-oxidant effects that led to the development of dysfunctional HDL in hyperlipidemic ApoE-/- mice, which might be one of the mechanisms how air pollution contributes to enhanced atherosclerosis.