Human plasminogen kringle 1-5 reduces atherosclerosis and neointima formation in mice by suppressing the inflammatory signaling pathway.
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-alpha (TNF-alpha) 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-alpha-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-kappaB 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.
Chang
P C
PC
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Wu
H L
HL
Lin
H C
HC
Wang
K C
KC
Shi
G Y
GY
D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002339:Carotid Arteries / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D010958:Plasminogen / Q000008:administration & dosage / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017539:Tunica Intima / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D001057:Apolipoproteins E; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C491499:plasminogen kringle 5; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D010958:Plasminogen