Midkine promotes atherosclerotic plaque formation through its pro-inflammatory, angiogenic and anti-apoptotic functions in apolipoprotein E-knockout mice

Background: A recent study suggested that midkine (MK), a heparin-binding growth factor, is associated with atherosclerosis progression in patients with artery disease. It has previously been reported that MK plays a critical role in neointima formation in a restenosis model, whereas the role of MK in the development of atherosclerosis has not been investigated. The present study assessed the effect of MK administration on the process of atherosclerotic plaque formation in apolipoprotein E-knockout (ApoE ^−/− ) mice. Methods and Results: Using an osmotic pump, human recombinant MK protein was intraperitoneally administered for 12 weeks in C57BL/6 ApoE ^−/− (ApoE ^−/− -MK) and ApoE ^+/+ mice fed a high-fat diet. Saline was administered to the control groups of ApoE ^−/− (ApoE ^−/− -saline) and ApoE ^+/+ mice. The atherosclerotic lesion areas in longitudinal aortic sections were significantly larger in ApoE ^−/− -MK mice than in ApoE ^−/− -saline mice. The aortic mRNA levels of pro-inflammatory and angiogenic factors, and the percentage of macrophages in aortic root lesions, were significantly higher in ApoE ^−/− -MK mice than in ApoE ^−/− -saline mice, whereas the percentage of apoptotic cells was significantly lower in ApoE ^−/− -MK mice than in ApoE ^−/− -saline mice. Conclusions: The systemic administration of MK in ApoE ^−/− mice promoted atherosclerotic plaque formation through pro-inflammatory, angiogenic, and anti-apoptotic effects. MK may serve as a potential therapeutic target for the prevention of atherosclerosis under atherogenic conditions.