Atherosclerotic vascular disease (AVD) is the leading cause of morbidity and mortality in the Western world. Although there is considerable controversy about the precise sequence of events leading to AVD, there is growing evidence that atherosclerotic lesions result from oxidative stress mediated by metabolic defects and, importantly, environmental insults. For example, environmental tobacco smoke (ETS) is an ubiquitous environmental toxicant and a significant risk factor for AVD. Metabolic lipid disorders, such as hypercholesterolemia (HC), are clearly causal in the development of atherosclerotic lesions. However, how both ETS and HC promote atherosclerotic lesion formation is poorly understood. A shared feature between ETS and HC is increased reactive oxygen and nitrogen species (RS, collectively) generation. Mitochondria are the primary source of cellular energy, and are also significant sources and targets of RS. Based upon preliminary studies that clearly demonstrate ETS, HC, and RS induce mitochondrial damage and that mitochondrial dysfunction hastens atherogenesis, we hypothesize that: ETS exposure preferentially damages vascular mitochondria, leading to mitochondrial dysfunction and the development of vascular lesions. Moreover, pre-existing HC promotes the progression of ETS-related lesions. To test this hypothesis, we will characterize the effects of ETS and HC on mitochondrial damage and function in vivo (Aim 1). We will then quantify the influence of mitochondrial dysfunction on the effects of ETS and HC (Aim 2). Finally, we will use pharmacologic and genetic approaches to delineate the role of antioxidant defenses on ETS-induced mitochondrial damage/dysfunction and lesion development (Aim 3). The proposed studies will elucidate the mechanisms of ETS-induced vascular lesions and provide new insights regarding the role of mitochondria in the development of atherosclerosis. These studies will provide valuable information regarding the potential mechanisms by which ETS increases the risk for AVD, which will enable the development of population risk assessment (e.g. characterize mtDNA damage) and therapeutic approaches aimed at AVD prevention in humans.
