From the INSERM U955, Département de Physiologie (S.A., A.H., N.M., E.M., V.A., F.W., G.D., J.B., R.M., S.A.) and Service de Cardiologie (J.L.D.-R.), Hôpital Henri Mondor, AP-HP, Université Paris-Est Creteil (UPEC), Créteil, France.
Arterioscler Thromb Vasc Biol. 2014 Feb;34(2):304-12. doi: 10.1161/ATVBAHA.113.302302. Epub 2013 Dec 12.
Carbon monoxide-releasing molecules (CORMs) represent a pharmacological alternative to CO gas inhalation. Here, we questioned whether CORM-3, a well-characterized water-soluble CORM, could prevent and reverse pulmonary hypertension (PH) in chronically hypoxic mice and in smooth muscle promoter 22 serotonin transporter mice overexpressing the serotonin transporter in smooth muscle cells (SMCs).
Treatment with CORM-3 (50 mg/kg per day once daily) for 3 weeks prevented PH, right ventricular hypertrophy, and distal pulmonary artery muscularization in mice exposed to chronic hypoxia and partially reversed PH in smooth muscle promoter 22 serotonin transporter mice by reducing Ki67 dividing pulmonary artery SMCs (PA-SMCs). In these models, CORM-3 markedly increased lung p21 mRNA and protein levels and p21-stained PA-SMCs. These effects contrasted with the transient pulmonary vasodilatation and rise in lung cGMP levels induced by a single injection of CORM-3 in mice exposed to acute hypoxia. Studies in cultured rat PA-SMCs revealed that the inhibitory effects of CORM-3 on cell growth were independent of cGMP formation but associated with increased p21 mRNA and protein levels. Protection against PH by CORM-3 required increased lung expression of p21, as indicated by the inability of CORM-3 to prevent chronic hypoxia-induced PH in p21-deficient mice and to alter the growth of PA-SMCs derived from p21-deficient mice. CORM-3-induced p21 overexpression was linked to p53 activation as assessed by the inability of CORM-3 to prevent PH and induce p21 expression in p53-deficient mice and in PA-SMCs derived from p53-deficient mice.
CORM-3 inhibits pulmonary vascular remodeling via p21, which may represent a useful approach for treating PH.
一氧化碳释放分子（CORMs）是一种替代 CO 气体吸入的药理学方法。在这里，我们质疑一种水溶性 CORM，即 CORM-3，是否可以预防和逆转慢性低氧小鼠的肺动脉高压（PH），以及在平滑肌启动子 22 中过表达 5-羟色胺转运体的平滑肌细胞（SMCs）中的 5-羟色胺转运体的 PH。
用 CORM-3（每天 50mg/kg 一次）治疗 3 周可预防慢性低氧小鼠的 PH、右心室肥厚和远端肺动脉肌化，并通过减少 Ki67 分裂的肺动脉平滑肌细胞（PA-SMCs）部分逆转平滑肌启动子 22 5-羟色胺转运体小鼠的 PH。在这些模型中，CORM-3 显著增加了肺 p21mRNA 和蛋白水平以及 p21 染色的 PA-SMCs。这些作用与单次注射 CORM-3 在急性低氧小鼠中引起的短暂肺血管舒张和肺 cGMP 水平升高形成对比。在培养的大鼠 PA-SMCs 中进行的研究表明，CORM-3 对细胞生长的抑制作用不依赖于 cGMP 的形成，但与增加的 p21mRNA 和蛋白水平有关。CORM-3 对 PH 的保护作用需要增加肺中的 p21 表达，这表明 CORM-3 不能预防慢性低氧诱导的 PH 缺失小鼠的 PH，也不能改变源自 p21 缺失小鼠的 PA-SMCs 的生长。CORM-3 诱导的 p21 过表达与 p53 激活有关，这可以通过 CORM-3 不能预防 PH 和在 p53 缺失小鼠以及源自 p53 缺失小鼠的 PA-SMCs 中诱导 p21 表达来评估。
CORM-3 通过 p21 抑制肺血管重塑，这可能是治疗 PH 的一种有用方法。
