Induction of heme oxygenase-1 in monocytes suppresses angiotensin II-elicited chemotactic activity through inhibition of CCR2: role of bilirubin and carbon monoxide generated by the enzyme.
Monocyte chemoattractant protein 1 (MCP-1) and the receptor for MCP-1, CCR2, play a pivotal role in the recruitment of monocytes to the subendothelium, which is the initial event in atherosclerosis. Heme oxygenase (HO) is a microsomal enzyme that catalyzes the degradation of heme into biliverdin, which is subsequently reduced to bilirubin, free iron, and carbon monoxide, and induction of HO-1 is potentially associated with cellular protection, especially against oxidative insults. The present study was designed to examine the role of HO-1 in monocytes in angiotensin II (Ang II)-induced chemotactic response. Ang II significantly stimulated superoxide formation in monocytes, as measured by nitro blue tetrazolium reduction assay, as well as the chemotactic response to MCP-1 with the increased expression of CCR2 determined by RT-PCR and western blotting analysis. Hemin-treated monocytes displayed an enhanced HO activity with the increased accumulation of bilirubin determined by immunostaining, when compared with control monocytes. The induction of HO-1 in monocytes suppresses not only Ang II-stimulated superoxide formation, but also Ang II-enhanced chemotactic activity. Exogenously applied bilirubin and carbon monoxide mimicked the inhibitory effect of HO-1 on the chemotactic response. These findings suggest that monocytic HO-1 might be a new therapeutic target for atherosclerosis.
D000804:Angiotensin II / Q000494:pharmacology*; D001663:Bilirubin / Q000378:metabolism* / Q000494:pharmacology; D002248:Carbon Monoxide / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects*; D004790:Enzyme Induction; D005786:Gene Expression Regulation / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
C515334:CCR2 protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D013481:Superoxides; D000804:Angiotensin II; D006427:Hemin; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D001663:Bilirubin