Cardiovascular Toxicity of Environmental Aldehydes
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Our central hypothesis is that environmental aldehydes induce and sustain cardiovascular inflammation. Due to limited metabolism, acute exposure triggers abnormal cardiovascular responses, whereas recurrent exposures establish a state of chronic inflammation. This exacerbates atherosclerosis, promotes thrombosis, enhances ischemic injury, and disrupts post-ischemic ventricular remodeling. Nonetheless, tissue-specific manifestations of aldehyde toxicity relate to a common set of molecular events associated with the activation of pro-inflammatory signaling pathways.
Overview of the Project
To test our central hypothesis, we have developed a comprehensive and integrated, experimental design. The Program is divided into 4 individual projects, and the overarching goal of each of these projects is to identify the mechanisms that regulate and determine cardiovascular toxicity of environmental aldehydes. We expect that an integrative analysis of the results obtained from the combination of projects is likely to provide a unified view of cardiovascular toxicity, its interacting determinants, and its interrelated manifestations.
Although several types of aldehydes are present in the environment, we are studying acrolein and trans-2-hexenal as model aldehydes. These aldehydes are the most abundant and toxic representatives of environmental electrophiles. Acrolein is the shortest and the most reactive of the a,b-unsaturated aldehyde series. It is generated by a variety of sources, and humans are exposed to acrolein through air, water, and food. Environmental exposure to other short chain aldehydes such as formaldehyde and acetaldehyde are also frequent; however, due to their lower reactivity, they are likely to be less toxic. Like acrolein, hexenal is also abundant in the environment and is present in high concentrations in a wide variety of food substances. Hexenal is an excellent model for studying the toxicity of medium chain aldehydes (C4 - C10). Longer (C > 10) unsaturated aldehydes are also present in food, particularly in deep fried fats, but some aspects of their toxicity are likely to overlap with hexenal. Hexenal is less reactive than acrolein and is likely to be metabolized by routes that differ from those of acrolein metabolism. Thus, parallel experiments with acrolein and hexenal will elucidate metabolic pathways and toxicological profiles for the entire range of aldehydes most prevalent in the environment (i.e., C3-C10 aldehydes).
We are studying the mechanisms of aldehyde toxicity related to the development or exacerbation of specific cardiovascular pathology in three different projects. These mechanisms could be understood most readily within the context of systemic and cardiovascular metabolism and detoxification, because the extent to which different cardiovascular tissues are exposed, and the intensity with which they respond, depends upon systemic factors that deliver aldehydes to individual cardiovascular sites and those by which local metabolic responses protect against aldehyde toxicity. We expect that successful completion of these studies will provide a unique assessment of cardiovascular risk due to exposure to environmental aldehydes.