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

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• 作者：Sarah Fayad-Kobeissi^a ; ^b ; ^{sarah.kobeissi@inserm.fr" class="auth_mail" title="E-mail the corresponding author} ; Johary Ratovonantenaina^a ; ^b ; ^{johary.ratovo@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Hubert Dabir&eacute ; ^c ; ^{hubert.dabire@inserm.fr" class="auth_mail" title="E-mail the corresponding author} ; Jayne Louise Wilson^a ; ^b ; ^{jayne-louise.wilson@inserm.fr" class="auth_mail" title="E-mail the corresponding author} ; Anne Marie Rodriguez^a ; ^b ; ^{anne-marie.rodriguez@inserm.fr" class="auth_mail" title="E-mail the corresponding author} ; Alain Berdeaux^c ; ^{alain.berdeaux@inserm.fr" class="auth_mail" title="E-mail the corresponding author} ; Jean-Luc Dubois-Rand&eacute ; ^d ; ^{jean-luc.dubois-rande@inserm.fr" class="auth_mail" title="E-mail the corresponding author} ; Brian E. Mann^e ; ^{b.mann@sheffield.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; Roberto Motterlini^a ; ^b ; ¹ ; ^{roberto.motterlini@inserm.fr" class="auth_mail" title="E-mail the corresponding author} ; Roberta Foresti^a ; ^b ; ¹ ; ^{roberta.foresti@inserm.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Carbon monoxide ; Carbon monoxide-releasing molecules ; Vascular activity ; Angiogenesis ; Heme oxygenase-1 ; p38 MAPK
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：102
• 期：Complete
• 页码：64-77
• 全文大小：2660 K

文摘

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.