Unraveling mechanisms of toxicant-induced oxidative stress in cardiovascular disease.

To date, numerous clinical studies examining correlations between oxidative stress biomarkers and cardiovascular diseases (CVD) have repeatedly suggested a role for oxidant injury in the pathogenesis of diseases such as atherosclerosis. Despite this, antioxidant supplementation trials have not demonstrated a reduction in disease progression. Nevertheless, small animal and epidemiological studies have linked exposures to certain toxicants with increased CVD risk involving putative oxidative stress mechanisms. A few prototypical vascular toxicants will be discussed as examples of toxicants that likely act via oxidative stress mechanisms. For discussion, we will classify these toxicants as those that induce direct (e.g., arsenic, nucleoside reverse transcriptase inhibitors) versus indirect (particulate matter, ozone) oxidative stress mechanisms, and those that likely induce CVD through both direct and indirect mechanisms (cigarette smoke). Finally, new findings in oxidative stress research, including the emerging importance of reactive sulfur species, hydrogen peroxide as a presumed endothelium-derived hyperpolarizing factors, etc., will be discussed, as well as the need to determine the role of toxicants in modulating these newly identified pathways. Moreover, given the lack of success in conclusively demonstrating the roles of oxidative stress in CVD risk stratification, research probing the roles of toxicant exposures in propagating CVD pathogenesis may be a novel approach for more conclusively delineating the causal role of oxidative stress in CVD initiation and progression.