Abstract 143: Endoplasmic Reticulum Stress Impairs Vascular Function Through Enhanced Nadph Oxidase Activity and Reduction in Enos Activity
Cardiovascular diseases are associated with the induction of endoplasmic reticulum (ER) stress. The induction of ER stress in C57BL/6J and p47phox-/- mice, by the injection of tunicamycin, greatly impaired vascular endothelium-dependent relaxation in C57BL/6J than in p47phox-/- mice. To determine the mechanism by which ER stress impairs endothelium function, we incubated mice primary endothelial cells from coronary arteries (ECs) with tunicamycin (1 μg/mL) for 6 h in the presence or absence of two ER stress inhibitors (Tudca, 500 μg/mL and PBA, 10 mM). Tunicamycin increased the phosphorylation of PERK and eIF2alpha, the expression of CHOP, ATF6 and Bip, Nox2/Nox4 mRNA levels, NADPH oxidase activity and superoxide anion levels. In addition, phosphorylated eNOS and nitrites levels were reduced with tunicamycin. All these events were prevented, at least partially, with the inhibition of ER stress. Tunicamycin treatment or the transfection of ECs with plasmids that express ATF6 or CHOP reduced the luciferase activity of a reporter plasmid containing the eNOS promoter. The ER stress induction reduced ERK1/2 phosphorylation and increased p38 MAPK phosphorylation. The inhibition of p38 MAPK restored the eNOS promoter activity and the eNOS phosphorylation, and reduced Bip but did not affect to ATF6 or CHOP expression.
Conclusion: ER stress induction impairs endothelial cell eNOS-dependent activity by oxidative stress and p38 MAPK-dependent mechanisms.
- © 2012 by American Heart Association, Inc.