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Published on: September 26, 2018
Midkine Promotes Atherosclerotic Plaque Formation Through Its Pro-Inflammatory, Angiogenic and Anti-Apoptotic
Yoshio Takemoto1,2, Mitsuru Horiba1,3,4, Masahide Harada1,5
1Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University.
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.
Insights
Midkine (MK) administration significantly accelerated atherosclerosis progression in ApoE-/- mice by promoting inflammation and angiogenesis while reducing apoptosis. These findings suggest MK as a potential therapeutic target for preventing atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Atherosclerosis Research
Background:
- Midkine (MK), a heparin-binding growth factor, is implicated in atherosclerosis progression.
- Previous research linked MK to neointima formation, but its role in atherosclerosis development was unclear.
Purpose of the Study:
- To investigate the effect of MK administration on atherosclerotic plaque formation.
- To assess MK's role in the development of atherosclerosis in apolipoprotein E-knockout (ApoE-/-) mice.
Main Methods:
- Human recombinant MK protein was administered intraperitoneally to ApoE-/- mice for 12 weeks.
- ApoE-/- mice on a high-fat diet received either MK or saline (control).
- Atherosclerotic lesion areas, inflammatory/angiogenic factors, macrophage infiltration, and apoptosis were analyzed.
Main Results:
- MK administration significantly increased atherosclerotic lesion areas in ApoE-/- mice.
- Pro-inflammatory and angiogenic mRNA levels were elevated in MK-treated mice.
- Macrophage percentage increased, while apoptotic cell percentage decreased in aortic root lesions of MK-treated mice.
Conclusions:
- Systemic MK administration promotes atherosclerotic plaque formation in ApoE-/- mice.
- MK exerts pro-inflammatory, angiogenic, and anti-apoptotic effects contributing to atherosclerosis.
- MK represents a potential therapeutic target for preventing atherosclerosis under atherogenic conditions.
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