Superfund Research Program
Role of Annexin II in Peripheral Vascular Disease
Project Leader: Richard R. Vaillancourt
Grant Number: P42ES004940
Funding Period: 2005-2010
- Project Summary
Project Summary (2005-2010)
Arsenic (As) is an inorganic environmental contaminant of major concern due to its ubiquitous presence. Chronic exposure to arsenic frequently results in peripheral vascular disease, as well as skin, lung, bladder, and kidney cancer. Recent evidence demonstrates that arsenite inhibits the production of plasmin, which is necessary to dissolve blood clots in the vasculature. Dr. Vaillancourt’s published studies with arsenic have demonstrated that the serine/threonine kinase, MEKK4, is involved in arsenic signal transduction, along with the calcium binding protein, annexin II. To understand the molecular mechanism by which arsenic causes its deleterious effects on the vascular system and how the activity ofannexin II contributes to arsenic toxicity, the researchers’ efforts have focused on characterizing the proteins that interact with and are regulated by annexin II. The hypothesis of this project is that annexin II plays a role in promoting arsenic dependent peripheral vascular disease by modulating the formation of plasmin. To test this hypothesis, the research team is taking the following approaches:
- Characterizing arsenic-dependent post-translational modifications of annexin II. They propose that arsenic methylation produces homocysteine, which chemically modifies annexin II, thus inhibiting the production of plasmin and promoting clotting of the microvasculature. They also propose that homocysteine-annexin II may be an indicator of arsenic exposure and they are exploring the possibility of using homocysteine-annexin II as a biomarker.
- Characterizing the interaction between annexin II and MEKK4. The researchers’ data indicate interaction between annexin II and MEKK4, resulting in MEKK4 activity. Since MEKK4 appears to function downstream of annexin II, the biochemical association between these proteins is being mapped to specific domains.
- Characterizing arsenic-dependent regulation of PAI-1 and PAI-2. The researchers propose that the ERK MAP kinase signaling pathway, regulated by annexin II and MEKK4, may be a mechanism for arsenic-dependent regulation of PAI expression.
- Assessing specific functions of annexin II. Researchers are creating a tissue-specific knockout mouse, selectively disrupting annexin II expression in smooth muscle cells, to evaluate arsenic toxicity in a whole animal. This research provides a further understanding of the importance of the arsenic-induced signaling processes and how it adversely affects the peripheral vascular system and promotes tissue injury.