Heme oxygenase-1 counteracts contrast media-induced endothelial cell dysfunction.
Endothelial cell (EC) dysfunction is involved in the pathogenesis of contrast-induced acute kidney injury, which is a major adverse event following coronary angiography. In this study, we evaluated the effect of contrast media (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 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 associated with an increase in NF-E2-related factor-2 (Nrf2) activity and reactive oxygen species (ROS). 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 acetylcysteine. 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. Thus, 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 novel approach in preventing CM-induced endothelial and organ dysfunction.
Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Nephrology, Department of Medicine, Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan.
Chao-Fu
CF
Chang
Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri-Columbia, Columbia, MO, USA.
Xiao-Ming
XM
Liu
Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri-Columbia, Columbia, MO, USA.
Kelly J
KJ
Peyton
Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri-Columbia, Columbia, MO, USA. Electronic address: durantew@health.missouri.edu.
William
W
Durante
D049109:Cell Proliferation / Q000187:drug effects; D003287:Contrast Media / Q000633:toxicity*; D017023:Coronary Angiography / Q000009:adverse effects / Q000379:methods; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D051547:Heme Oxygenase-1 / Q000494:pharmacology / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D020298:U937 Cells
D003287:Contrast Media; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
Endothelial cells; Heme oxygenase-1; Inflammation; Iodixanol (PubChem CID: 3724); Iopamidol (PubChem CID: 65492); N-acetyl-l-cysteine (PubChem CID: 12035); Radiocontrast media; Sodium diatrizoate (PubChem CID: 23672589); Tin protoporphyrin-IX (PubChem CID: 3000478)