Grants and Contracts Details
Cardiovascular disease (CVD),the leading cause of death in the United States, can be characterized by the disruption of the endothelium as an initiating event of this inflammatory process. The vascular endothelium is important as a barrier from blood constituents and is extremely susceptible to environmental insults. Within the last decade, epidemiological evidence has linked exposure to pollutants such as polycyclic aromatic hydrocarbons (PAHs) to CVD progression. Oxidative stress, resulting from a local imbalance between the formation of reactive oxygen species (ROS) and antioxidant defenses, is an important contributor to atherogenesis. The oxidation hypothesis proposes that development of vascular diseases such as atherosclerosis involve stimulation of oxidative-sensitive signaling pathways mediated by intracellular ROS. PAHs have long been shown to produce intracellular ROS, thus possessing the ability to activate a number of inflammatory signaling pathways. One such oxidative-sensitive pathway and a key regulatory transcription factor in the inflammatory process of CVD is signal transducers and activators of transcription (STAT). STAT has been shown to regulate the transcription of inflammatory mediators such as monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and heat shock protein 70 (Hsp70). Little is known about dietary interventions capable of alleviating PAH-induced cytotoxicity. Polyphenols derived from plant sources such as grapes and teas have been shown to reduce atherosclerosis via reduction of ROS. It is hypothesized that PAHs can contribute to vascular inflammation by increasing STAT signaling and that nutrients, such as phenolics that possess antioxidant or anti-inflammatory properties, can down-regulate PAHinduced STAT signaling pathways, leading to reduced inflammatory events. To investigate these hypotheses, three specific aims are being proposed: Specific Aim 1: To test the hypothesis that phenolics can modulate increases in ROS mediated by PAHs in the vascular endothelium. Specific Aim 2: To test the hypothesis that PAHs will lead to the activation of the STAT family of transcription factors through the production of ROS and that phenolics can down-regulate these events. Specific Aim 3: To test the hypothesis that PAHs cause increases in STAT controlled inflammatory mediators that have been shown to contribute to CVD progression and can also be down-regulated by phenolics.
|Effective start/end date||7/1/06 → 6/30/08|
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