Absence of cytoglobin promotes multiple organ abnormalities in aged mice.
Absence of cytoglobin promotes multiple organ abnormalities in aged mice.
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DOI：
10.1038/srep24990
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发表时间：
2016-05-05
影响因子：
4.6
通讯作者：
Kawada N
中科院分区：
文献类型：
--
作者：
Thuy le TT;Van Thuy TT;Matsumoto Y;Hai H;Ikura Y;Yoshizato K;Kawada N
细胞珠蛋白（Cygb）被确定在肝星状细胞（HSC）和周细胞的所有器官;然而，Cygb对细胞功能的影响仍不清楚。在这里，我们报告了Cygb−/−小鼠多个器官的自发性和年龄依赖性畸形。26%的年轻Cygb−/−小鼠（<1岁）表现出心脏肥大，肾脏或卵巢囊性疾病，失去平衡，肝纤维化和淋巴瘤。此外，71.3%（82/115）的老年Cygb−/−小鼠（1-2岁）表现出异常，如心脏肥大和多器官癌症发展;相比之下，5.8%（4/68）的老年野生型（WT）小鼠有异常（p < 0.0001）。有趣的是，血清和尿液分析表明，Cygb−/−小鼠中一氧化氮代谢产物的浓度显著增加，导致氧化应激和抗氧化防御系统失衡，而NG-单甲基-L-精氨酸治疗可以逆转这种失衡。在原代HSC和老年Cygb−/−小鼠的肝脏中发现了衰老表型和DNA损伤的证据。此外，与HSC+/+相比，HSC−/−在与小鼠Hepa 1-6细胞共培养时显示出IL-6和趋化因子mRNA的高表达。因此，周细胞中Cygb的缺乏引起器官异常，可能是通过一氧化氮和抗氧化防御系统的紊乱以及通过加速细胞衰老。
Cytoglobin (Cygb) was identified in hepatic stellate cells (HSCs) and pericytes of all organs; however, the effects of Cygb on cellular functions remain unclear. Here, we report spontaneous and age-dependent malformations in multiple organs of Cygb−/− mice. Twenty-six percent of young Cygb−/− mice (<1 year old) showed heart hypertrophy, cystic disease in the kidney or ovary, loss of balance, liver fibrosis and lymphoma. Furthermore, 71.3% (82/115) of aged Cygb−/− mice (1–2 years old) exhibited abnormalities, such as heart hypertrophy and cancer development in multiple organs; by contrast, 5.8% (4/68) of aged wild-type (WT) mice had abnormalities (p < 0.0001). Interestingly, serum and urine analysis demonstrated that the concentration of nitric oxide metabolites increased significantly in Cygb−/− mice, resulting in an imbalance in the oxidative stress and antioxidant defence system that was reversed by NG-monomethyl-L-arginine treatment. A senescent phenotype and evidence of DNA damage were found in primary HSCs and the liver of aged Cygb−/− mice. Moreover, compared with HSC+/+, HSC−/− showed high expression of Il-6 and chemokine mRNA when cocultured with mouse Hepa 1–6 cells. Thus, the absence of Cygb in pericytes provokes organ abnormalities, possibly via derangement of the nitric oxide and antioxidant defence system and through accelerated cellular senescence.