Heme oxygenase‐1 counteracts contrast media‐induced endothelial cell dysfunction (855.1)

Abstract

Endothelial cell (EC) dysfunction contributes to the pathogenesis of contrast media (CM)‐induced acute kidney injury, which is a major adverse event following coronary angiography. In this study, we evaluated the effect of CM on human EC proliferation, migration, and inflammation, and determined if heme oxygenase‐1 (HO‐1) influences the biological actions of CM. We found that three distinct iodine‐based CM, including high‐osmolar (diatrizoate), low‐osmolar (iopamidol), and iso‐osmolar (iodixanol), stimulated the expression of HO‐1 protein and mRNA. The induction of HO‐1 was dependent on the concentration and duration of CM exposure and associated with an increase in NF‐E2‐related factor‐2 (Nrf2) activity and reactive oxygen species (ROS) production. CM also stimulated HO‐1 promoter activity and this was prevented by mutating the antioxidant responsive element or by overexpressing dominant‐negative Nrf2. In addition, the CM‐mediated induction of HO‐1 and activation of Nrf2 was abolished by N‐acetyl‐L‐cysteine. Finally, CM inhibited the proliferation and migration of ECs and stimulated the expression of intercellular adhesion molecule‐1 and the adhesion of monocytes on ECs. Inhibition or silencing of HO‐1 exacerbated the anti‐proliferative and inflammatory actions of CM but had no effect on the anti‐migratory effect. In conclusion, the present study demonstrates that the induction of HO‐1 via the ROS‐Nrf2 pathway counteracts the anti‐proliferative and inflammatory actions of CM. Therapeutic approaches targeting HO‐1 may provide a promising approach in preventing CM‐induced endothelial and organ dysfunction.Grant Funding Source: Supported by NIH grant HL59976 and a grant from the Department of Health, Taipei City Government