[Introduction]
Resistin was initially proposed as an adipokine in murine models that links obesity and insulin resistance, but the role of resistin in human is debatable. Despite of growing evidence about connection between human resistin and atherosclerosis, the role of resistin in atherosclerotic progression has not been clarified due to the absence of appropriate animal model. Here, we cloned rabbit resistin which is closer to human resistin than murine one, and elucidated the causal relationship between resistin and atherosclerosis with suggestions regarding underlying mechanism.
[Methods and Results]
In order to use rabbit model for studying the role of resistin in atherosclerosis, we cloned rabbit resistin which proved similarity to human resistin both in amino-acid sequence(71.3% identity) and in tissue expression pattern (high expression in bone marrow and circulating monocytes). In rabbit atherosclerosis models including aorta of hypercholesterolemic rabbit, balloon injured carotid artery and collared carotid artery, macrophages highly expressed resistin in atherosclerotic plaque, just like in human situation. Then, to clarify the causal relationship, we transferred resistin gene by adenoviral vector to collared rabbit carotid artery and found that resistin significantly increases neointimal growth (I/M area ratio 2.0, p=0.02) and macrophage accumulation. Finally, to demonstrate the mechanism we performed various in vitro experiments and found that resistin functions as a chemotactic agent for monocytes, and also increases monocyte-endothelial adhesion by stimulating VCAM-1 expression on endothelial cell and its counter part, integrin α4β1, on monocytes. It also stimulated monocyte proliferation, invasion, and expression of pro-atherosclerotic cytokines such as IL-8 and VEGF.
[Conclusion]
Resistin which is induced to express in macrophages of atherosclerotic lesion, stimulates interaction of endothelial and monocytes and enhance infiltration of macrophages, leading to progression of atherosclerosis.
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