Interaction of carbon monoxide-releasing ruthenium carbonyl CORM-3 with plasma fibronectin
Interaction of carbon monoxide-releasing ruthenium carbonyl CORM-3 with plasma fibronectin
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DOI：
10.1016/j.tiv.2018.03.010
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发表时间：
2018-08-01
影响因子：
3.2
通讯作者：
Uemura, Koichi
中科院分区：
文献类型：
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作者：
Aki, Toshihiko;Unuma, Kana;Uemura, Koichi
吸入的一氧化碳（CO）气体是剧毒的，但人体产生低水平的CO用于血管调节和其他目的。考虑到低浓度CO气体对一系列病理性损伤的保护作用，CO释放分子（CORMs）已经在体外和体内疾病模型中得到开发和研究。在CORMs中，CORM-3 [Ru(CO)(3)Cl（甘氨酸）]是一种钌羰基化合物，因其水溶性和适合体内应用而被广泛研究。由于CO气体最突出的特征之一是其抗纤维化作用，我们研究了CORM-3对小鼠胚胎成纤维细胞（mef）的影响。1 mM CORM-3作用于MEFs后，24 h内胶原I和胶原III的合成减少，证实了其抗纤维化作用。令我们惊讶的是，CORM-3导致细胞相关的血浆纤维连接蛋白（FN）快速（在1小时内）从细胞中分离，这与血浆纤维连接蛋白抗还原低聚物的形成有关。用纯化的FN在体外复制了血浆FN的这种异常寡聚化。此外，我们发现RuCl3，而不是另一种水溶性CORM， CORM- a1 [Na2H3BCO2]，也在体外低聚血浆FN。通过长时间（72小时）暴露于CORM-3，从血清中去除FN可显著改善细胞死亡，这表明FN寡聚化对细胞死亡具有不利作用。综上所述，我们首次发现FN是corm -3相互作用的血浆蛋白，CORM-3-FN相互作用参与成纤维细胞的死亡。
Inhaled carbon monoxide (CO) gas is highly toxic, but the human body produces low levels of CO for vasoregulation and other purposes. Given the established protective roles of low concentrations of CO gas against a panel of pathological insults, CO-releasing molecules (CORMs) have been developed and examined in disease models both in vitro and in vivo. Among CORMs, CORM-3 [Ru(CO)(3)Cl(glycinate)], a ruthenium carbonyl compound, has been extensively studied since it is water-soluble and is suitable for in vivo application. As one of the most prominent features of CO gas is its anti-fibrotic effect, we examined the effects of CORM-3 on mouse embryonic fibroblasts (MEFs). The application of 1 mM CORM-3 to MEFs resulted in the decreased syntheses of collagens I and III within 24 h, confirming an anti-fibrotic effect. To our surprise, CORM-3 caused a rapid (within 1 h) dissociation of cell-associated plasma fibronectin (FN) from the cells, which is associated with formation of a reduction-resistant oligomer of plasma FN. This aberrant oligomerization of plasma FN was reproduced using purified FN in vitro. Furthermore, we showed that RuCl3, but not another water-soluble CORM, CORM-A1 [Na2H3BCO2], also oligomerized plasma FN in vitro. FN depletion from the serum substantially ameliorates cell death by prolonged (72 h) exposure to CORM-3, suggesting a detrimental role of FN oligomerization on cell death. Taken together, we reveal for the first time that FN is a CORM-3-interactive plasma protein, and that the CORM-3-FN interaction is involved in the death of fibroblasts.