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Systemic delivery of microRNA-181b inhibits nuclear factor-?B activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice.

ABSTRACT: Activated nuclear factor (NF)-?B signaling in the vascular endothelium promotes the initiation and progression of atherosclerosis. Targeting endothelial NF-?B may provide a novel strategy to limit chronic inflammation.To examine the role of microRNA-181b (miR-181b) in endothelial NF-?B signaling and effects on atherosclerosis.MiR-181b expression was reduced in the aortic intima and plasma in apolipoprotein E-deficient mice fed a high-fat diet. Correspondingly, circulating miR-181b in the plasma was markedly reduced in human subjects with coronary artery disease. Systemic delivery of miR-181b resulted in a 2.3-fold overexpression of miR-181b in the aortic intima of apolipoprotein E-deficient mice and suppressed NF-?B signaling revealed by bioluminescence imaging and reduced target gene expression in the aortic arch in apolipoprotein E-deficient/NF-?B-luciferase transgenic mice. MiR-181b significantly inhibited atherosclerotic lesion formation, proinflammatory gene expression and the influx of lesional macrophages and CD4+ T cells in the vessel wall. Mechanistically, miR-181b inhibited the expression of the target gene importin-?3, an effect that reduced NF-?B nuclear translocation specifically in the vascular endothelium of lesions, whereas surprisingly leukocyte NF-?B signaling was unaffected despite a 7-fold overexpression of miR-181b. Our findings uncover that NF-?B nuclear translocation in leukocytes does not involve importin-?3, but rather importin-?5, which miR-181b does not target, highlighting that inhibition of NF-?B signaling in the endothelium is sufficient to mediate miR-181b's protective effects.Systemic delivery of miR-181b inhibits the activation of NF-?B and atherosclerosis through cell-specific mechanisms in the vascular endothelium. These findings support the rationale that delivery of miR-181b may provide a novel therapeutic approach to treat chronic inflammatory diseases such as atherosclerosis.

SUBMITTER: Sun X

PROVIDER: S-EPMC4051320 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Systemic delivery of microRNA-181b inhibits nuclear factor-κB activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice.

Sun Xinghui X He Shaolin S Wara A K M AKM Icli Basak B Shvartz Eugenia E Tesmenitsky Yevgenia Y Belkin Nathan N Li Dazhu D Blackwell Timothy S TS Sukhova Galina K GK Croce Kevin K Feinberg Mark W MW

Circulation research 20131001 1

<h4>Rationale</h4>Activated nuclear factor (NF)-κB signaling in the vascular endothelium promotes the initiation and progression of atherosclerosis. Targeting endothelial NF-κB may provide a novel strategy to limit chronic inflammation.<h4>Objective</h4>To examine the role of microRNA-181b (miR-181b) in endothelial NF-κB signaling and effects on atherosclerosis.<h4>Methods and results</h4>MiR-181b expression was reduced in the aortic intima and plasma in apolipoprotein E-deficient mice fed a hig ...[more]

PMID: 24084690

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Project description:BackgroundVinexin ? is a novel adaptor protein that regulates cellular adhesion, cytoskeletal reorganization, signal transduction, and transcription; however, the exact role that vinexin ? plays in atherosclerosis remains unknown.Methods and resultsImmunoblot analysis showed that vinexin ? expression is upregulated in the atherosclerotic lesions of both patients with coronary heart disease and hyperlipemic apolipoprotein E-deficient mice and is primarily localized in macrophages indicated by immunofluorescence staining. The high-fat diet-induced double-knockout mice exhibited lower aortic plaque burdens than apolipoprotein E-/- littermates and decreased macrophage content. Vinexin ? deficiency improved plaque stability by attenuating lipid accumulation and increasing smooth muscle cell content and collagen. Moreover, the bone marrow transplant experiment demonstrated that vinexin ? deficiency exerts atheroprotective effects in hematopoietic cells. Consistent with these changes, the mRNA expression of proinflammatory cytokines were downregulated in vinexin ?-/- apolipoprotein E-/- mice, whereas the anti-inflammatory M2 macrophage markers were upregulated. The immunohistochemical staining and in vitro experiments showed that deficiency of vinexin ? inhibited the accumulation of monocytes and the migration of macrophages induced by tumor necrosis factor ?-stimulated human umbilical vein endothelial cells as well as macrophage proliferation. Finally, the inhibitory effects exerted by vinexin ? deficiency on foam cell formation, nuclear factor ?B activation, and inflammatory cytokine expression were largely reversed by constitutive Akt activation, whereas the increased expression of the nuclear factor ?B subset promoted by adenoviral vinexin ? was dramatically suppressed by inhibition of AKT.ConclusionsVinexin ? deficiency attenuates atherogenesis primarily by suppressing vascular inflammation and inactivating Akt-nuclear factor ?B signaling. Our data suggest that vinexin ? could be a therapeutic target for the treatment of atherosclerosis.

Dataset Information

Systemic delivery of microRNA-181b inhibits nuclear factor-?B activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice.

Publications

Systemic delivery of microRNA-181b inhibits nuclear factor-κB activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice.

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