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Neointima formation in a restenosis model is suppressed in midkine-deficient mice.

ABSTRACT: Neointima formation is a common feature of atherosclerosis and restenosis after balloon angioplasty. To find a new target to suppress neointima formation, we investigated the possible role of midkine (MK), a heparin-binding growth factor with neurotrophic and chemotactic activities, in neointima formation. MK expression increased during neointima formation caused by intraluminal balloon injury of the rat carotid artery. Neointima formation in a restenosis model was strongly suppressed in MK-deficient mice. Continuous administration of MK protein to MK-deficient mice restored neointima formation. Leukocyte recruitment to the vascular walls after injury was markedly decreased in MK-deficient mice. Soluble MK as well as that bound to the substratum induced migration of macrophages in vitro. These results indicate that MK plays a critical role in neointima formation at least in part owing to its ability to mediate leukocyte recruitment.

SUBMITTER: Horiba M

PROVIDER: S-EPMC289157 | biostudies-literature | 2000 Feb

REPOSITORIES: biostudies-literature

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Neointima formation in a restenosis model is suppressed in midkine-deficient mice.

Horiba M M Kadomatsu K K Nakamura E E Muramatsu H H Ikematsu S S Sakuma S S Hayashi K K Yuzawa Y Y Matsuo S S Kuzuya M M Kaname T T Hirai M M Saito H H Muramatsu T T

The Journal of clinical investigation 20000201 4

Neointima formation is a common feature of atherosclerosis and restenosis after balloon angioplasty. To find a new target to suppress neointima formation, we investigated the possible role of midkine (MK), a heparin-binding growth factor with neurotrophic and chemotactic activities, in neointima formation. MK expression increased during neointima formation caused by intraluminal balloon injury of the rat carotid artery. Neointima formation in a restenosis model was strongly suppressed in MK-defi ...[more]

PMID: 10683378

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Project description:Atherogenesis and arterial remodeling following mechanical injury are driven by inflammation and mononuclear cell infiltration. The binding of immune complexes (ICs) to immunoglobulin (Ig)-Fc gamma receptors (Fc?Rs) on most innate and adaptive immune cells induces a variety of inflammatory responses that promote atherogenesis. Here, we studied the role of Fc?RIII in neointima formation after arterial injury in atherosclerosis-prone mice and compared the outcome and mechanism to that of Fc?RIII in diet-induced "chronic" atherosclerosis. Fc?rIII-/-/Apoe-/- and control Apoe-/- mice were subjected to wire-induced endothelial denudation of the carotid artery while on high-fat diet (HFD). Fc?rIII deficiency mitigated neointimal plaque formation and lesional macrophage accumulation, and enhanced neointimal vascular smooth muscle cell (VSMC) numbers. This went along with a reduced expression of tumor necrosis factor-? (TNF-?), monocyte chemoattractant protein-1 (MCP-1/CCL2), and vascular cell adhesion molecule-1 (VCAM-1) in the neointimal lesions. Interestingly, in a chronic model of diet-induced atherosclerosis, we unraveled a dichotomic role of Fc?RIII in an early versus advanced stage of the disease. While Fc?rIII deficiency conferred atheroprotection in the early stage, it promoted atherosclerosis in advanced stages. To this end, Fc?rIII deficiency attenuated pro-inflammatory responses in early atherosclerosis but promoted these events in advanced stages. Analysis of the mechanism(s) underlying the athero-promoting effect of Fc?rIII deficiency in late-stage atherosclerosis revealed increased serum levels of anti-oxidized-LDL immunoglobulins IgG2c and IgG2b. This was paralleled by enhanced lesional accumulation of IgGs without affecting levels of complement-activated products C5a or C5ar1, Fc?RII, and Fc?RIV. Moreover, Fc?rIII-deficient macrophages expressed more Fc?rII, Tnf-?, and Il-1? mRNA when exposed to IgG1 or oxLDL-IgG1 ICs in vitro, and peripheral CD4+ and CD8+ T-cell levels were altered. Collectively, our data suggest that deficiency of activating Fc?RIII limits neointima formation after arterial injury in atherosclerosis-prone mice as well as early stage chronic atherosclerosis, but augments late-stage atherosclerosis suggesting a dual role of Fc?RIII in atherogenic inflammation.

Dataset Information

Neointima formation in a restenosis model is suppressed in midkine-deficient mice.

Publications

Neointima formation in a restenosis model is suppressed in midkine-deficient mice.

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