Abstract
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.
Highlights
Cygb displays nitric oxide dioxygenase (NOD) activity[7,8]
Cyst of uterus, 6 M; mesenteric cyst, 10 M (i); heart hypertrophy, 22 M (j). (C) Representative haematoxylin and eosin (H&E)-stained sections of Cygb−/− mice with adenoma (a) and adenocarcinoma (b) of the lung; hepatocellular carcinoma (HCC) (c); lymphoma in the liver (d, arrow), spleen (e), and mesenteric lymph node (f); intestinal adenoma (g); intestine lymphoma (h), which was metastatic to the lung (i, arrows; right inset, × 1200); kidney cysts (j); H&E and Sirius Red and Fast Green (SiR-FG) staining of a renal myomatous lesion (k, l) and spleen fibrosis (m, n; right inset, × 800); hypertrophy of cardiomyocytes in KO mice compared with WT mice (o, WT; p, KO)
Histopathological analysis of lungs from Cygb−/− mice at 18 M revealed that the primary tumour types were adenoma (Fig. 1Ca) and adenocarcinoma (Fig. 1Cb)
Summary
Cygb displays nitric oxide dioxygenase (NOD) activity[7,8]. Smagghe and colleagues examined the NOD activity of various globins in their oxy-ferrous state and showed that human Ngb and Cygb, rice nsHb (riceHb1), Synechocystis Hb (cyanoglobin, SynHb), and horse heart Mb rapidly destroy NO in vitro; among these, Cygb showed the highest consumption rate[9]. Latina et al reported that Cygb is transcriptionally regulated by Δ Np63 in primary epithelial cells (keratinocytes) and in cancer cells (H226, MCF-7) under normal proliferating conditions (normoxia) and following oxidative stress[18]. These reports suggest that in addition to functioning as a gas carrier, Cygb might act as a cytoprotective factor under conditions of hypoxia and oxidative stress. To study the biological function of Cygb at the tissue level, we generated Cygb-deficient (Cygb−/−) mice and reported their high susceptibility to tumour development in the liver and lungs when treated with N, N-diethylnitrosamine (DEN)[19]. The presence of Cygb in the pericytes of all organs serves an important function in maintaining homeostasis of the antioxidant system
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