Principal Investigator: Sanjay Srivastava
Funding Mechanism: National Institutes of Health- Grant
ID number: 1R01HL120746-01
Award Date: 9/19/2013
Institution: University of Louisville
Cigarette smoking and, potentially, smokeless tobacco use are associated with an increase in cardiovascular disease (CVD) risk. Nevertheless, the tobacco constituents that mediate the cardiovascular toxicity of tobacco use remain unknown. Although several studies have examined the effect of cigarette smoke on surrogate markers of heart disease, the direct effect of tobacco smoke and smokeless tobacco on atherosclerosis, the underlying cause of CVD, has not been rigorously studied. Because CVD is a chronic disease that develops over several years, biomarkers of tobacco-induced cardiovascular injury are needed to assess CVD risk in a timeframe sufficient for product evaluation; biomarkers of exposure to specific tobacco product constituents must also be identified. The goal of this project is to identify biomarkers of exposure to tobacco products and relate them to atherosclerosis. Specific aims are: (1) to examine tobacco-induced atherosclerosis in mice and rats exposed to tobacco smoke and smokeless tobacco; and (2) to delineate the contribution of certain harmful and potentially harmful constituents (HPHCs) to atherosclerosis development. To achieve the first aim, investigators will expose apoE-null mice and rats to varying intensities of tobacco smoke and smokeless tobacco in order to: identify urinary metabolites of exposure-derived aldehydes and determine how they relate to the extent and duration of exposure and to atherosclerotic lesion formation and stability; evaluate the effects of gender, species, and exposure duration on the relationship between biomarkers of injury and biomarkers of exposure; and identify specific indices of atherosclerosis and thrombosis and determine how these biomarkers of injury are related to biomarkers of exposure. To achieve the second aim, investigators will examine changes in cholesterol metabolism, platelet function and atherosclerotic lesion formation, composition and nature in apoE-null mice exposed to individual tobacco constituents (i.e., nicotine, acrolein, crotonaldehyde); investigators will also determine how removal of these constituents affects atherogenesis and whether an increase in exposure to aldehydes and related reactive chemicals exacerbates atherosclerosis. This project will contribute to the development of validated animal models to establish standard toxicity changes and the discovery of novel biomarkers of cardiovascular injury that can be associated with measures of tobacco exposure. These findings will be useful in evaluating the contribution of HPHCs to tobacco product toxicity; assessing the extent of harm reduction associated with potentially modified risk products; informing policies for regulating HPHCs in smokeless tobacco, cigarettes and emerging tobacco products; and informing the design of future human studies for evaluating the cardiovascular effects of tobacco use.