Human plasminogen kringle 1–5 reduces atherosclerosis and neointima formation in mice by suppressing the inflammatory signaling pathway

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.