Molecular Mechanism of Acrolein-Induced Vascular Toxicity: Role of PPAR gamma and

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DESCRIPTION (provided by applicant): Acrolein a major environmental pollutant classified by the Environmental Protection Agency (EPA) as a high-priority air/water toxic and an endogenous peroxidation product has been linked to impaired vascular reactivity, leading to atherosclerotic changes at concentrations documented in human disease, or doses similar to human oral total aldehyde intake. The precise mechanism of acrolein mediated vascular alteration is not clear, but a possible association with an increased superoxide activity and reduced antioxidant defense has been proposed. Atherosclerotic changes in the vasculature are usually preceded by early signs of inflammation. This process involves nitric oxide (NO) and oxygen free radicals. Vascular NAD(P)H oxidase plays an important role as the major source of oxygen free radical generation. Peroxisome proliferator activated receptor gamma (PPARγ), a nuclear transcription factor, regulates inflammatory response via modulating the transcription of inflammatory genes. PPARγ down regulates NAD(P)H-dependent superoxide generation via transcriptional regulation of gp91phox and p47phox subunits of NAD(P)H oxidase. Inflammatory response is a crucial balance between NO and superoxide, and regulation of vascular response is mostly NO dependent. Therefore, an interaction may persist between PPARγ, NAD(P)H oxidase and NO/nitric oxide synthase (NOS) system in acrolein toxicity. In this study, we hypothesize that acrolein alters PPARγ-dependent regulation of NAD(P)H oxidase, increases superoxide generation and thus offsets the PPARγ,-NAD(P)H,- and NO/NOS-dependent anti-inflammatory responses. The aims of the study are: (1) To determine the role of PPARγ in acrolein-induced vascular toxicity, (2) To establish the role of PPARγ in NAD(P)H-dependent superoxide generation and (3) To determine the PPARγ,-NAD(P)H,- and NO/NOS-dependent modulation of inflammation in acrolein- induced vascular toxicity. Acrolein treated Sprague-Dawley rats, gp91phox and p47 phox knockout mice, and NOS knockout mice will be utilized to determine changes in blood pressure and vascular responses by telemetry and hemodynamic analysis. NAD(P)H oxidase expression, activity and superoxide generation will be investigated. Inflammatory markers will be investigated by examining IL-2, COX-1, NFkappaB and NOS. This study will allow us to understand the mechanism of acrolein-induced vascular toxicity and thus the inflammatory mechanism of atherosclerosis. Incidents of cardiovascular diseases (CVD) are higher in African- Americans and may be partially due to lower socioeconomic status of the minorities and residence in areas with increased exposure to environmental pollutants. This study will broaden our understanding of contribution of environmental pollutants to CVD, and provides information on the possibility of involvement of PPARγ-and NAD(P)H -dependent regulation of inflammatory processes which ultimately will lead to better and more specific treatments for CVD among vulnerable population.