研究内容

①Impact of plasma oxidized low-density lipoprotein removal on atherosclerosis

oxidized low-density lipoprotein (oxLDL) has been proposed to be involved in atherosclerosis in clinical research. Then, we hypothesized that removal of oxLDL from plasma can ameliorate atherosclerosis.

Lectin-like oxLDL receptor 1 (LOX-1), an oxLDL receptor, was overexpressed ectopically in the liver of apoE knockout mice. These LOX-1 overexpressed mice prevented atherosclerotic progression. (Fig. 1)

(Ishigaki Y, Katagiri H, Gao J, et al. Circulation 118:75-83, 2008)

②Involvement of endoplasmic stress protein C/EBP homologous protein in arteriosclerosis acceleration

In recent years, attention has been focused on the association arteriosclerosis and ER stress. Newly synthesized protein form ribosome is translated into the ER, is modified to folding, glycosylation and disulfide formation, resulted in desired conformation. The ER monitors protein folding called “quality control” of protein. If the capacity of ER processing is overload, ER stress response is induced. One of the ER stress response is inducing cellular apoptosis.

CHOP (C/EBP homolougus protein) is known to induce cellular apoptosis in response to ER stress. CHOP deficient mice significantly suppressed neointimal formation in femoral artery. CHOP deficiency also inhibited aortic plaque formation in apoE knockout mice. Bone marrow transplantation experiments revealed that CHOP in both the vascular wall cells (endothelial cell, smooth muscle cell, etc.) and the blood cells (monocyte, macrophage, etc.) are important for atherosclerosis progression. (Figure 2)

(Gao J, Ishigaki Y, Yamada T, Kondo K, et al. Circulation 124:830-9, 2011)

③Bach1 deficiency and pancreaticβ-cell function

Pancreatic β-cell produces mainly insulin. β-cell have very low intrinsic antioxidant enzyme capacity compared with other tissues, is sensitive to oxidative stress.

BTB and CNC homology 1 (Bach 1) is a transcriptional repressor of antioxidative enzyme, such as heme oxygenase-1 (HO-1). Bach 1 is proposed to be involved in the insulin secretion and the survival of pancreatic βcells. We conducted the effect of Bach 1 on pancreatic β-cell using Bach 1 knockout mice. Bach1 deficiency protects amelioration of Alloxan-induced hyperglycemia. The mechanism of the protection is to preserve pancreatic insulin content due to reduction of apoptosis of β-cell and upregulation of HO-1 expression.(Fig. 3)

(Kondo K, Gao J, Ishigaki Y, et al. Am J Physiol Endocrinol Metab 305:E641-8, 2013)