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Aging enhances the basal production of IL-6 and CCL2 in vascular smooth muscle cells.

ABSTRACT: Increased circulating cytokine levels are a prominent feature of aging that may contribute to atherosclerosis. However, the role vascular cells play in chronic inflammation induced by aging is not clear. Here, we examined the role of aging on inflammatory responses of vascular cells.In an ex vivo culture system, we examined the inflammatory response of aortas from young (2-4 months) and aged (16-18 months) mice under nonstimulatory conditions. We found that basal levels of interleukin-6 were increased in aged aortas. Aged aortic vascular smooth muscle cells (VSMC) exhibited a higher basal secretion of interleukin-6 than young VSMC. Gene and protein expression analysis revealed that aged VSMC exhibited upregulation of chemokines (eg, CCL2), adhesion molecules (eg, intracellular adhesion molecule 1), and innate immune receptors (eg, Toll-like receptor [TLR] 4), which all contribute to atherosclerosis. Using VSMC from aged TL4(-/-) and Myd88(-/-) mice, we demonstrate that signaling via TLR4 and its signal adaptor, MyD88, are in part responsible for the age-elevated basal interleukin-6 response.Aging induces a proinflammatory phenotype in VSMC due in part to increased signaling of TLR4 and MyD88. Our results provide a potential explanation as to why aging leads to chronic inflammation and enhanced atherosclerosis.

SUBMITTER: Song Y

PROVIDER: S-EPMC3241880 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Aging enhances the basal production of IL-6 and CCL2 in vascular smooth muscle cells.

Song Yang Y Shen Hua H Schenten Dominik D Shan Peiying P Lee Patty J PJ Goldstein Daniel R DR

Arteriosclerosis, thrombosis, and vascular biology 20111027 1

<h4>Objective</h4>Increased circulating cytokine levels are a prominent feature of aging that may contribute to atherosclerosis. However, the role vascular cells play in chronic inflammation induced by aging is not clear. Here, we examined the role of aging on inflammatory responses of vascular cells.<h4>Methods and results</h4>In an ex vivo culture system, we examined the inflammatory response of aortas from young (2-4 months) and aged (16-18 months) mice under nonstimulatory conditions. We fou ...[more]

PMID: 22034510

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Project description:BackgroundAmong older adults, arterial aging is the major factor contributing to increased risk for cardiovascular disease-related morbidity and mortality. The chronic vascular inflammation that accompanies aging causes diffuse intimal-medial thickening of the arterial wall, thus increasing the vulnerability of aged vessels to vascular insults. Milk fat globule-epidermal growth factor 8 (MFG-E8) is a biomarker for aging arteries. This integrin-binding glycoprotein, induced by angiotensin II, facilitates vascular smooth muscle cell (VSMC) proliferation and invasion in aging vasculatures. This study investigated whether MFG-E8 directly mediates the initial inflammatory responses in aged arteries or VSMCs.MethodsA model of neointimal hyperplasia was induced in the common carotid artery (CCA) of aged mice to exacerbate age-associated vascular remodeling. Recombinant MFG-E8 (rMFG-E8) was administered to the injured artery using Pluronic gel to accentuate the effect on age-related vascular pathophysiology. The MFG-E8 level, leukocyte infiltration, and proinflammatory cell adhesion molecule (CAM) expression in the arterial wall were evaluated through immunohistochemistry. By using immunofluorescence and immunoblotting, the activation of the critical proinflammatory transcription factor nuclear factor (NF)-κB in the injured CCAs was analyzed. Immunofluorescence, immunoblotting, and quantitative real-time polymerase chain reaction were conducted using VSMCs isolated from the aortas of young and aged mice to assess NF-κB nuclear translocation, NF-κB-dependent gene expression, and cell proliferation. The extent of intimal-medial thickening in the injured vessels was analyzed morphometrically. Finally, Transwell migration assay was used to examine VSMC migration.ResultsEndogenous MFG-E8 expression in aged CCAs was significantly induced by ligation injury. Aged CCAs treated with rMFG-E8 exhibited increased leukocyte extravasation, CAM expression, and considerably increased NF-κB activation induced by rMFG-E8 in the ligated vessels. Exposure of early passage VSMCs from aged aortas to rMFG-E8 substantially increased NF-κB activation, proinflammatory gene expression, and cell proliferation. However, rMFG-E8 attenuated VSMC migration.ConclusionsMFG-E8 promoted the proinflammatory phenotypic shift of aged VSMCs and arteries, rendering the vasculature prone to vascular diseases. MFG-E8 may constitute a novel therapeutic target for retarding the aging processes in such vessels.

Dataset Information

Aging enhances the basal production of IL-6 and CCL2 in vascular smooth muscle cells.

Publications

Aging enhances the basal production of IL-6 and CCL2 in vascular smooth muscle cells.

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