Abstract 378: Contribution of Unfolded Protein Response in Arsenic-Induced Endothelial Activation and Atherosclerois
Epidemiological and animal studies suggest that exposure to arsenic contaminated water exacerbates atherosclerosis. However, the mechanisms by which arsenic exerts its atherogenic effects are not known. We observed that chronic (1 μM; 4 days) or acute (20 μM; 2-6 hours) exposure of sodium arsenite to human umbilical vein endothelial cells (HUVEC) increased the surface expression of adhesion molecules ICAM-1, VCAM-1 and E-Selectin by 1.2-1.5-fold; leukocyte adhesion by 1.5-3.5 fold; leukocyte trans-endothelial migration by 1.7-2.5-fold; and mRNA expression of IL-8 by 5-25-fold. Similarly, exposure of human aortic endothelial cells and mouse aortic endothelial cells to arsenic also caused endothelial activation. Arsenic also enhanced the unfolded protein response (UPR) in endothelial cells as evident by the phosphorylation of IRE-1 and activation of its downstream proteins JNK and NF-kappaB; nuclear translocation of ATF6, and increased expression of molecular chaperones GRP78 and HERP. SiRNA-mediated knockdown of IRE-1 attenuated arsenic-induced NF-kappaB activation and IL-8 expression, but did not affect JNK phosphorylation. Adenoviral transfection with ATF-6 upregulated GRP78 and decreased the expression of IL-8. Similarly, pre-incubation of endothelial cells with phenyl butyric acid (PBA; 5 mM, 16h), a chemical chaperone of protein folding, significantly (P<0.05) prevented arsenic-induced leukocyte adhesion, trans-endothelial migration and IL-8 expression. Feeding of apoE-null mice with PBA for 16 weeks inhibited the arsenic-induced UPR in atherosclerotic lesions; expression of adhesion molecules on endothelial cells lining the atherosclerotic lesions; lesional and systemic inflammation; and prevented the arsenic-induced exacerbation of lesion formation by 90% (P<0.05). Together, these data suggest that arsenic causes endothelial activation and exacerbates atherosclerosis by triggering UPR and chemical chaperones of protein folding prevent arsenic-induced exacerbation of atherogenesis.
Author Disclosures: S.D. Sithu: None. N.S. Wickramasinghe: None. E. Vladykovskaya: None. P. Haberzettl: None. A. Agarwal: None. M. Winner: None. S.E. D’Souza: None. S. Srivastava: None.
- © 2015 by American Heart Association, Inc.