Abstract 3760: Atherogenic Affects Of Arsenic: Role Of Endoplasmic Reticulum Stress And Unfolded Protein Response
Arsenic is a global water contaminant and EPA has listed arsenic as a high priority hazardous substance in the United States. Epidemiological studies suggest that chronic arsenic ingestion increases cardiovascular disease in humans, particularly, carotid atherosclerosis. However, mechanisms of arsenic-induced atherogenesis are unknown. We examined the effect of arsenic exposure on early lesion formation in apoE-null mice maintained on water supplemented with (0, 1, 5 and 50 ppm; 3–16 weeks of age) sodium arsenite. Arsenic, did not affect plasma cholesterol but decreased the triglycerides by 18±4 % (P<0.05). NMR analysis of the lipoproteins showed a significant decrease in the abundance of large VLDL particle (>60 nm diameter). Despite a significant decrease in plasma triglyceride, atherosclerotic lesion formation was significantly increased (2– 4 fold; P<0.05 for all doses) in the aortic sinus and the aortic arch of the arsenic-fed mice in a dose dependent manner. Immunohistochemical analysis showed significant increase in the accumulation of macrophages, expression of MCP-1 and unfolded protein response (UPR) dependent activating transcription factor (ATF)-4 and ATF3, in the lesions of arsenic (1ppm) exposed mice. In vitro, arsenic (5–25 μM), significantly increased the expression of ICAM-1, transmigration of differentiated monocytes and expression of the pro-inflammatory cytokine IL-8 in vascular endothelial cells (vEC). Arsenic, also increased the expression of ER-chaperones Grp 78, HERP and calnexin (2– 6 fold; P<0.01). Examination of the effect of arsenic on UPR showed that arsenic, induced the splicing of IRE-1 dependent, bZIP transcription factor XBP-1(alarm phase) and increased the phosphorylation of eIF2α (PERK mediated adaptive phase) by 3 fold (P<0.01) in vEC. Arsenic also induced the expression of the downstream effecter proteins of eIF2α-ATF3 (8 fold; P<0.01) and pro-apoptotic protein CHOP (4 fold; P<0.01) in vEC. Chemical chaperone, phenyl butyric acid (PBA), attenuated the arsenic-induced expression of ATF3 (>90%; P<0.001) and CHOP (>90%; P<0.001). These data suggest that ER-stress and UPR could exacerbate arsenic-induced vascular inflammation and promote atherogenesis.