Absence of cytoglobin, a novel marker of hepatic stellate cells, promotes multiple organ abnormality in aged mice via nitric oxide induced senescence

Although cytoglobin (Cygb) was firstly explored in hepatic stellate cells (HSCs) and then found in pericytes of all organs, how Cygb affects their cellular functions in physiological environment remains obscure. Previously, we... [ view full abstract ]

Although cytoglobin (Cygb) was firstly explored in hepatic stellate cells (HSCs) and then found in pericytes of all organs, how Cygb affects their cellular functions in physiological environment remains obscure. Previously, we created Cygb-deficient (Cygb^-/-) mice and reported the promotion of fibrosis and tumors in the liver under either diet or chemical treatment. Here, we report the spontaneous and age-dependent multiple organ malformations in Cygb^-/- mice. From 1 to 2 years old, 71.3% (82/115) of Cygb^‑/‑ mice including males and females exhibited abnormalities such as heart hypertrophy and cancer development in multiple organs, including the liver, lung, lymph nodes and intestine, compared with 5.8% (4/68) in wild-type (WT) mice (p<0.0001). Serum and urine analysis demonstrated that concentration of nitric oxide (NO) metabolites, i.e., nitrite and nitrate, significantly increased in Cygb^‑/‑ mice compared to WT counterparts. Consequently, increased expression of oxidant genes, such as myeloperoxidase, inducible nitric oxide synthetize, and eosinophil peroxidase, but down-regulation antioxidant genes including glutathione peroxidase, superoxide dismutase-2, and serine peptidase inhibitor were explored by PCR array and quantitative real-time PCR. Importantly, accelerated expression of genes related to senescence-associated secretory phenotype including p16, p21, Gro-α, Cxcl-9, and Il1β were found in the liver and γH2AX in liver and primary HSCs of aged Cygb^‑/‑ mice. Moreover, we observed increased expression of Ccl-2 and -3 at mRNA level when primary WT-hepatocytes were co-cultured with HSC^Cygb-null, but not with HSC^Cygb-WT. In conclusion: Absence of Cygb in pericytes provokes organ abnormalities due to possible derangement of NO and antioxidant system induced senescence.