title: Absence of cytoglobin promotes multiple organ abnormalities in aged mice.
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 N(G)-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.
authors.affiliation: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors.forename: Le Thi Thanh
authors.initials: le TT
authors.lastname: Thuy
authors.affiliation: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors.forename: Tuong Thi
authors.initials: TT
authors.lastname: Van Thuy
authors.affiliation: Department of Medical Nutrition, Graduate School of Human Life Science, Osaka City University, Osaka, Japan.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors.forename: Hoang
authors.initials: H
authors.lastname: Hai
authors.affiliation: Department of Pathology, Takatsuki General Hospital, Takatsuki, Osaka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ikura
authors.affiliation: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.|PhoenixBio Co. Ltd., Hiroshima, Japan.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yoshizato
authors.affiliation: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Kawada
mesh_terms: D000375:Aging; D000825:Animal Structures / Q000473:pathology*; D000818:Animals; D000078842:Cytoglobin; D005914:Globins / Q000172:deficiency*; D051379:Mice; D018384:Oxidative Stress; D026361:Reactive Nitrogen Species / Q000032:analysis
chemical_list: C000627265:CYGB protein, human; C000627267:Cygb protein, mouse; D000078842:Cytoglobin; D026361:Reactive Nitrogen Species; D005914:Globins