Published online before print September 20, 2007

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(American Journal of Pathology. 2007;171:1705-1712.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070471

Requirement of Apelin-Apelin Receptor System for Oxidative Stress-Linked Atherosclerosis

Tatsuo Hashimoto^*, Minoru Kihara^*, Nozomi Imai^*, Shin-ichiro Yoshida^*, Hiroaki Shimoyamada, Hiroaki Yasuzaki^*, Junji Ishida, Yoshiyuki Toya^*, Yoshihiro Kiuchi^¶, Nobuhito Hirawa^*, Kouichi Tamura^*, Takuya Yazawa, Hitoshi Kitamura, Akiyoshi Fukamizu and Satoshi Umemura^*

From the Departments of Medical Science and Cardiorenal Medicine^* and Pathobiology, and the Laboratory Animal Center,^¶ Yokohama City University Graduate School of Medicine and School of Medicine, Yokohama; and the Center for Tsukuba Advanced Research Alliance and the Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan

The recently identified endogenous peptide apelin and its specific apelin receptor (APJ) are currently being considered as potential regulators in vascular tissue. Previously, we reported apelin mediates phosphorylation of myosin light chain and elicits vasoconstriction in vascular smooth muscle. In this study, physiological roles of the apelin-APJ system were investigated on atherosclerosis. In APJ and apolipoprotein E double-knockout (APJ^–/–ApoE^–/–) mice fed a high-cholesterol diet, atherosclerotic lesions were dramatically reduced when compared with APJ^+/+ ApoE^–/– mice, in the absence of an effect of cholesterol levels. Immunohistochemical detection of smooth muscle cells, using a smooth muscle -actin antibody, showed greatly reduced staining for these cells in lesions of APJ^–/–ApoE^–/– mice fed a high-cholesterol diet. Vascular production of superoxide radicals and the expression of nicotinamide-adenine dinucleotide phosphate oxidase subunits were decreased in APJ^–/–ApoE^–/– mice compared with APJ^+/+ApoE^–/– mice fed a standard normal diet. In vascular smooth muscle cells, apelin induced nicotinamide-adenine dinucleotide phosphate oxidase subunit expression. Apelin also induced vascular smooth muscle cell proliferation, which was inhibited by superoxide dismutase or diphenylene iodonium. The apelin-APJ system is a mediator of oxidative stress in vascular tissue, and thus we propose it to be a critical factor in atherogenesis under high-cholesterol dietary conditions. APJ deficiency is preventative against oxidative stress-linked atherosclerosis.

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