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Abstract 440: Heat Shock Proteins Prevent Environmental Chemicals-induced Endothelial Activation And Injury


 Environmental pollution accounts for nine million premature deaths worldwide every year and cardiovascular disease is the leading cause environmental pollution-associated deaths. Our previous studies have shown that exposure to combustion-derived chemicals (e.g., acrolein), petroleum products-derived chemicals (e.g., benzene) and metalloid such as arsenic exacerbates atherosclerosis in mice.
 In vitro
 studies suggest that these chemicals endothelial activation and injury, at least in part, by inducing endoplasmic reticulum stress. To examine how endothelial cells cope with environmental chemicals-induced toxicity, we performed transcriptomic analyses of human aortic endothelial cells (HAEC) exposed to acrolein (10 μM),
 t,t
 -muconaldehyde (MA, reactive metabolite of benzene, 10 μM), and arsenic (20 μM). Our data show that exposure of HAEC to these chemicals significantly induced the expression (log 2FC = 2-13-fold) of heat shock proteins -
 Hspa1a, Hspa1b, Hspa6
 , and
 Hspa7
 , the molecular chaperones which keep the proteins in their native structures. MA-induced transcription of HSPs in HAEC was accompanied by the induction (log 2FC = 1-3) of oxidative stress-responsive genes superoxide dismutase 1, heme oxygenase-1, cyclooxygenase-2, and
 Akr1b10
 ; ER-stress responsive gene
 Atf3; and
 adhesion molecules
 Icam-1
 and
 P-selectin;
 and downregulation of endothelial nitric oxide synthase (
 Nos
 3, log 2FC = -0.4). Like HAEC, MA also significantly induced
 Hspa1b1
 and
 Atf3
 (log 2FC= 2.3 and 0.7 respectively). siRNA-mediated knockdown of
 Hspa1b
 in HAEC significantly increased MA-induced transcription of
 Icam-1
 and leukocyte adhesion to endothelial cells, abundance of ATF3 protein, endothelial cell apoptosis, and attenuated MA-induced downregulation of
 Nos
 3 gene. The reactome analysis of MA-treated HAEC suggested that heat shock factor-1 (HSF-1) is the transcriptional regulator of
 Hspa1a
 and
 Hspa1b
 . Western blotting of MA-treated HAEC showed that MA upregulates as well as phosphorylates HSF-1, which attenuates IL-6 expression by activating ATF3. Collectively, these data suggest that HSPs prevent environmental chemicals-induced endothelial toxicity by preventing oxidative stress, ER-stress, inflammation, and depletion of
 Nos3
 .
