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Human plasminogen kringle 1–5 reduces atherosclerosis and neointima formation in mice by suppressing the inflammatory signaling pathway
Author(s) -
CHANG P. C.,
WU H. L.,
LIN H. C.,
WANG K. C.,
SHI G. Y.
Publication year - 2010
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2009.03671.x
Subject(s) - neointima , angiostatin , apolipoprotein e , tumor necrosis factor alpha , angiogenesis , ligation , inflammation , chemistry , umbilical vein , endocrinology , cancer research , medicine , restenosis , biochemistry , in vitro , disease , stent
Summary. Background: Activation of vascular endothelial cells plays an important role in atherogenesis and plaque instability. Recent research has demonstrated that late‐stage inhibition of plaque angiogenesis by angiostatin (kringle 1–4) reduces macrophage accumulation and slows the progression of advanced atherosclerosis. Kringle 1–5 (K 1–5 ) is a variant of angiostatin that contains the first five kringle domains of plasminogen. Objective: To investigate whether K 1–5 has an inhibitory effect on early‐stage atherosclerosis, using the apolipoprotein E (ApoE)‐deficient mouse model and a carotid artery ligation model. Methods: ApoE‐deficient mice received K 1–5 treatment for 4 weeks, and the severity of aortic atherosclerosis was measured. In the ligation model, the left common carotid arteries of C57BL/6 mice were ligated near the carotid bifurcation, and the mice received K 1–5 for 4 weeks. Human umbilical vein endothelial cells were pretreated with K 1–5 before tumor necrosis factor‐α (TNF‐α) treatment to explore the anti‐inflammatory effect of K 1–5 . Results: The areas of the lesion in the aortas of ApoE‐deficient mice that received K 1–5 treatment were notably decreased, and the formation of carotid neointima in the C57BL/6 mice was decreased by treatment with K 1–5 . Expression of TNF‐α‐induced intercellular adhesion molecule‐1 and vascular cell adhesion molecule‐1 was inhibited by K 1–5 treatment, possibly via downregulation of translocation of nuclear factor‐κB and expression of reactive oxygen species. Conclusions: K 1–5 reduced atherosclerosis and neointima formation in mice, possibly through inhibition of intercellular adhesion molecule‐1 and vascular cell adhesion molecule‐1 expression in endothelial cells.