Carbon monoxide induces chromatin remodelling to facilitate endothelial cell migration.
Vascular injury to vessel endothelial cells (EC), caused by either mechanical damage or chronic inflammation, is still awaiting effective therapies. In the present study we hypothesised that carbon monoxide (CO) acts on the nuclear receptor Rev-erbα to induce chromatin modification and endothelial cell migration. We demonstrate that administration of low, safe doses of exogenous CO enhances endothelial cell (EC) migration, which occurs in part through chromatin remodelling and histone H3 acetylation. Further, we show that the effects of CO are dependent on inhibition of phosphorylation of glycogen synthase kinase-3 β (GSK3β), activation of haem synthesis, and increased expression of Rev-erbα. Rev-erbα is a haem-containing transcription factor which in response to CO binds to target DNA, recruits the Histone Deacetylase/nuclear Receptor Corepressor (HDAC/N-CoR) complex, and regulates transcription of genes responsible for endothelial cell migration and angiogenesis. Decreased levels of Rev-erbα in chimeric mice after bone marrow transplant from Rev-erbα following bone marrow transplantation from rev-erb+/- mice resulted in loss of protective effects of CO against neointima formation after wire injury. Collectively, CO modifies chromatin structure through enhanced acetylation of histone H3 via a GSK3β-Rev-erbα-mediated pathway to increase EC migration. We propose that CO enhances vessel repair following injury in part by regulating EPC/EC motility via Rev-erbα. Thus, inhaled CO may be beneficial in the treatment of vascular syndromes associated with dysregulated thrombosis, wound healing, and angiogenesis.
Mailin
M
Li
David
D
Gallo
Eva
E
Csizmadia
Leo E
LE
Otterbein
Barbara Wegiel, PhD, Department of Surgery, Harvard Medical School, Department of Surgery, Beth Israel Deaconess Medical Center, 3 Blackfan Circle CLS #601, Boston, MA 02215, USA, Tel.: +1 617 735 2846, Fax: +1 617 735 2844, E-mail: bwegiel@bidmc.harvard.edu 
Barbara
B
Wegiel
D000107:Acetylation; D000280:Administration, Inhalation; D000818:Animals; D002248:Carbon Monoxide / Q000008:administration & dosage*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D056970:Co-Repressor Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D015533:Transcriptional Activation / Q000187:drug effects; D018183:Transplantation Chimera; D057772:Vascular System Injuries / Q000628:therapy*; D014945:Wound Healing / Q000187:drug effects
D056970:Co-Repressor Proteins; D006657:Histones; D046912:Multiprotein Complexes; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D002248:Carbon Monoxide; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D006655:Histone Deacetylases
Carbon monoxide; migration; nuclear receptor; vascular repair