title: Vascular and angiogenic activities of CORM-401, an oxidant-sensitive CO-releasing molecule.
abstract: Carbon monoxide (CO) is generated by heme oxygenase-1 (HO-1) and displays important signaling, anti-apoptotic and anti-inflammatory activities, indicating that pharmacological agents mimicking its action may have therapeutic benefit. This study examined the biochemical and pharmacological properties of CORM-401, a recently described CO-releasing molecule containing manganese as a metal center. We used in vitro approaches, ex-vivo rat aortic rings and the EA.hy926 endothelial cell line in culture to address how CORM-401 releases CO and whether the compound modulates vascular tone and pro-angiogenic activities, respectively. We found that CORM-401 released up to three CO/mole of compound depending on the concentration of the acceptor myoglobin. Oxidants such as H2O2, tert-butyl hydroperoxide or hypochlorous acid increased the CO liberated by CORM-401. CORM-401 also relaxed pre-contracted aortic rings and vasorelaxation was enhanced in combination with H2O2. Consistent with the release of multiple CO molecules, CORM-401-induced vasodilation was three times higher than that elicited by CORM-A1, which exhibits a similar half-life to CORM-401 but liberates only one CO/mole of compound. Furthermore, endothelial cells exposed to CORM-401 accumulated CO intracellularly, accelerated migration in vitro and increased VEGF and IL-8 levels. Studies using pharmacological inhibitors revealed HO-1 and p38 MAP kinase as two independent and parallel mechanisms involved in stimulating migration. We conclude that the ability of CORM-401 to release multiple CO, its sensitivity to oxidants which increase CO release, and its vascular and pro-angiogenic properties highlight new advances in the design of CO-releasing molecules that can be tailored for the treatment of inflammatory and oxidative stress-mediated pathologies.
authors.affiliation: Université Paris-Est, Faculté de Medicine, Créteil 94000, France; INSERM, U955, Equipe 12, Créteil 94000, France. Electronic address: sarah.kobeissi@inserm.fr.
authors.forename: Sarah
authors.initials: S
authors.lastname: Fayad-Kobeissi
authors.affiliation: Université Paris-Est, Faculté de Medicine, Créteil 94000, France; INSERM, U955, Equipe 12, Créteil 94000, France. Electronic address: johary.ratovo@gmail.com.
authors.forename: Johary
authors.initials: J
authors.lastname: Ratovonantenaina
authors.affiliation: INSERM, U955, Equipe 3, Créteil 94000, France. Electronic address: hubert.dabire@inserm.fr.
authors.forename: Hubert
authors.initials: H
authors.lastname: Dabiré
authors.affiliation: Université Paris-Est, Faculté de Medicine, Créteil 94000, France; INSERM, U955, Equipe 12, Créteil 94000, France. Electronic address: jayne-louise.wilson@inserm.fr.
authors.forename: Jayne Louise
authors.initials: JL
authors.lastname: Wilson
authors.affiliation: Université Paris-Est, Faculté de Medicine, Créteil 94000, France; INSERM, U955, Equipe 12, Créteil 94000, France. Electronic address: anne-marie.rodriguez@inserm.fr.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Rodriguez
authors.affiliation: INSERM, U955, Equipe 3, Créteil 94000, France. Electronic address: alain.berdeaux@inserm.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Berdeaux
authors.affiliation: AP-HP, Hôpital Henri Mondor-A. Chenevier, Service Hospitalier, Créteil 94000, France. Electronic address: jean-luc.dubois-rande@inserm.fr.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dubois-Randé
authors.affiliation: Department of Chemistry, University of Sheffield, Sheffield S3 7HF, United Kingdom. Electronic address: b.mann@sheffield.ac.uk.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Mann
authors.affiliation: Université Paris-Est, Faculté de Medicine, Créteil 94000, France; INSERM, U955, Equipe 12, Créteil 94000, France. Electronic address: roberto.motterlini@inserm.fr.
authors.forename: Roberto
authors.initials: R
authors.lastname: Motterlini
authors.affiliation: Université Paris-Est, Faculté de Medicine, Créteil 94000, France; INSERM, U955, Equipe 12, Créteil 94000, France. Electronic address: roberta.foresti@inserm.fr.
authors.forename: Roberta
authors.initials: R
authors.lastname: Foresti
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D002248:Carbon Monoxide / Q000819:agonists / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D016877:Oxidants / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D043925:Angiogenesis Inducing Agents; D016877:Oxidants; D002248:Carbon Monoxide
keywords: Angiogenesis; Carbon monoxide; Carbon monoxide-releasing molecules; Heme oxygenase-1; Vascular activity; p38 MAPK