Premium
Hypochlorous acid‐induced heme oxygenase‐1 gene expression promotes human endothelial cell survival
Author(s) -
Liu Xiaoming,
Wei Yong,
Peyton Kelly J.,
Wang Hong,
Johnson Fruzsina K.,
Johnson Robert A.,
Durante William
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.628.1
Subject(s) - hypochlorous acid , heme oxygenase , myeloperoxidase , heme , chemistry , catalase , gene knockdown , biochemistry , microbiology and biotechnology , oxidative stress , enzyme , inflammation , apoptosis , biology , immunology
Hypochlorous acid (HOCl) is a unique oxidant generated by the enzyme myeloperoxidase that contributes to endothelial cell (EC) dysfunction and death in atherosclerosis. Since myeloperoxidase localizes with heme oxygenase‐1 (HO‐1) in and around ECs of atherosclerotic lesions, the present study investigated whether there was an interaction between these two enzymes in vascular endothelium. Treatment of human ECs with the myeloperoxidase product HOCl stimulated a concentration‐ and time‐dependent increase in HO‐1 mRNA, protein, and promoter activity, and carbon monoxide synthesis that was preceded by a marked rise in Nrf2 protein. The HOCl‐mediated increase in HO‐1 promoter activity was blocked by mutating the antioxidant response element in the promoter or by overexpressing a dominant‐negative mutant of Nrf2. The induction of Nrf2 or HO‐1 by HOCl was prevented by N‐acetyl‐L‐cysteine. Finally, treatment of ECs with HOCl stimulated cell death that was potentiated by the HO inhibitor tin protoporphyrin‐IX or by the selective knockdown of HO‐1. These results demonstrate that HOCl induces HO‐1 gene transcription via the redox‐dependent activation of Nrf2 to counteract HOCl‐mediated toxicity. The ability of HOCl to activate Nrf2 and stimulate HO‐1 gene expression may represent a critical adaptive response to maintain EC viability at sites of vascular inflammation and atherosclerosis. Supported by NIH and AHA.