Vascular and angiogenic activities of CORM-401, an oxidant-sensitive CO-releasing molecule

• Published in: Biochemical pharmacology 2016-02, Vol.102, p.64-77
• Main Authors: Fayad-Kobeissi, Sarah, Ratovonantenaina, Johary, Dabiré, Hubert, Wilson, Jayne Louise, Rodriguez, Anne Marie, Berdeaux, Alain, Dubois-Randé, Jean-Luc, Mann, Brian E., Motterlini, Roberto, Foresti, Roberta
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inducing Agents - chemistry; Angiogenesis Inducing Agents - pharmacology; Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - metabolism; Aorta, Thoracic - secretion; Carbon monoxide; Carbon Monoxide - agonists; Carbon Monoxide - metabolism; Carbon monoxide-releasing molecules; Cell Line, Tumor; Dose-Response Relationship, Drug; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - secretion; Heme oxygenase-1; Humans; Male; Oxidants - chemistry; Oxidants - pharmacology; p38 MAPK; Rats; Rats, Wistar; Vascular activity
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2015.12.014

[Display omitted] 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.