Functional analysis of cytoglobin that is expressed and induced in liver cirrhosis

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Cytoglobin consists of a new class of hexacoordinate globin superfamily, which was recently discovered by a proteomics approach for the rat hepatic stellate cell, an unique fibroblastic cell in the liver. Unlike hemoglobin, myoglobin and neuroglobin, cytoglobin is ubiquitously expressed in several organs including the liver, pancreas, kidney, spleen, intestine and lung, although its detailed localization is unclarified. Immunohistochemistry and immunoelectronmicroscopy revealed that cytoglobin is uniquely localized in fibroblast-like cells in splanchnic organs, namely vitamin A-storing cell lineage, but neither in epithelial cells, endothelial cells, muscle cells, blood cells, macrophages, nor dermal fibroblasts. Expression of cytoglobin was upregulated in fibrotic lesions of pancreas and kidney in which activated fibroblast-like cells or myofibroblasts increased in number. In cultured hepatic stellate cells, cytoglobin expression was augmented by the stimulation with serum, platelet-derived growth factor-BB and transforming growth factor-beta 1. These results indicate that cytoglobin is a tissue hemoglobin uniquely localized in splanchnic fibroblastic cell lineage and may play a role in fibrotic organ disorder. Additional experiments obtained by purified and crystallized cytoglobin revealed that this protein bind oxygen, nitric oxide and carbon monoxide in a manner similar to myoglobin. Thus, cytoglobin is a novel globin that play a role in oxygen transport in visceral myofibroblasts and in contrast myoglobin seems to be a muscle cell-specific oxygen carrier.