Apoptosis of vascular smooth muscle cells in vascular remodelling and atherosclerotic plaque rupture

IL-19 is a recently described, putative anti-inflammatory cytokine which had previously been ascribed to be leukocyte specific. IL-19 is not detected in normal artery, but we detected IL-19 in multiple cell types in human atherosclerotic plaque suggesting a role for this interleukin in atherosclerosis. The purpose of this study was to determine whether administration of exogenous IL-19 could attenuate development of pre-formed atherosclerotic plaque, and to identify potential molecular mechanisms. LDLR-/- mice were fed high-fat diet for 12 weeks and then administered with 10ng/g/day IL-19 or PBS for an additional 8 weeks. En face analysis demonstrated that IL-19 could halt, but not reverse existing plaque (26.7+/-1.7%, 41.03+/-3.1%, 23.70+/-2.6% for baseline, PBS control, and IL-19-treated mice). Foam cell formation by macrophages and vascular smooth muscle cells (VSMC) is a hallmark event during atherosclerosis. Nothing has been reported regarding IL-19 effects on macrophage or VSMC lipid uptake; we therefore investigated whether IL-19 affects macrophage and VSMC cholesterol handling. Addition of IL-19 to wild-type bone marrow derived macrophages (BMDM) significantly promoted oxLDL uptake, conversely, BMDM from IL-19-/- mice had significantly less oxLDL uptake compared to wild-type BMDM. Addition of IL-19 to wild type BMDM significantly increased expression of scavenger receptor B1 (SR-B1), and decreased expression of inflammatory cytokines TNFα, IL-12b, MCP1. Interestingly, converse results were obtained with VSMC, as addition of IL-19 to wild-type VSMC decreased uptake of oxLDL ( p<0.05 ) and decreased expression of scavenger receptor CD36. VSMC isolated from IL-19-/- mice had increased uptake of oxLDL (p<0.0001). It is reported that M2 macrophages participate in plaque regression. IL-19 decreased IL-12b and significantly promoted the polarization of anti-inflammatory M2 phenotype in BMDM as evidenced by the increased expression of YM1 and IL-10 mRNA. These data demonstrate that IL-19 can inhibit progression of existing atherosclerotic plaque by modulating lipid metabolism in VSMC and macrophages and by promoting macrophage differentiation into an alternative, anti-inflammatory M2 phenotype.

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P677Defective autophagy in vascular smooth muscle cells promotes an unstable atherosclerotic plaque phenotype and increased expression of mitophagy markers in Apo E−/− mice

European Heart Journal ◽

10.1093/eurheartj/ehx501.p677 ◽

2017 ◽

Vol 38 (suppl_1) ◽

Author(s):

H. Nahapetyan ◽

J. Faccini ◽

M. Elbaz ◽

M.H. Grazide ◽

E. Mucher ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Atherosclerotic Plaque ◽

Muscle Cells ◽

Apo E ◽

Plaque Phenotype ◽

Unstable Atherosclerotic Plaque

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P737The pro-inflammatory environment of the atherosclerotic plaque influences the biology of vascular smooth muscle cells in by regulating calcium-calmodulin dependent Kinase II

Cardiovascular Research ◽

10.1093/cvr/cvu098.158 ◽

2014 ◽

Vol 103 (suppl 1) ◽

pp. S135.2-S135

Author(s):

A S Maione ◽

M R Rusciano ◽

D Sorriento ◽

M Soprano ◽

L Maresca ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Atherosclerotic Plaque ◽

Muscle Cells ◽

Calcium Calmodulin Dependent

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Abstract 429: The Effects of Fluvastatin and Methyl-β-Cyclodextrin-Mediated Cholesterol Depletion on the Biomechanics of Vascular Smooth Muscle Cells in Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.429 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Hanna J Sanyour ◽

Zhongkui Hong

Keyword(s):

Smooth Muscle ◽

Cell Adhesion ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Atherosclerotic Plaque ◽

Muscle Cells ◽

Cell Cortex ◽

Cholesterol Depletion ◽

Progression Of Atherosclerosis

Atherosclerosis is a leading cause of death worldwide. Phenotypic shifting, alteration in cell adhesion, and migration toward inflammatory site of blood vessel wall are all critical contributions of vascular smooth muscle cells (VSMC) to the progression of atherosclerosis. Knowing that cholesterol is a main participant of fatty deposition in atherosclerotic lesions, cholesterol’s role in orchestrating cell migration, mechanics and spreading has grown more apparent. Growing evidences suggests that cholesterol loaded into VSMC in atherosclerosis is much larger than previously known, and about 40% of the total foam cells in the atherosclerotic plaque were VSMC-derived. Emerging studies have increasingly categorized cholesterol as major player in regulating VSMC stiffness and N-Cadherin mediated cell-cell adhesions. Modulating their activity or expression may block VSMC migration during the progression of atherosclerosis. In this study, the effects of a 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitor, fluvastatin and Methyl-β-Cyclodextrin-Mediated (MβCD) cholesterol depletion on VSMCs N-cadherin adhesion and cellular stiffness were addressed. VSMCs cholesterol quantification and lactate dehydrogenase assays demonstrated significant reduction in total cellular cholesterol content by approx. 67% for fluvastatin and 40% for MβCD. The atomic force microscope (AFM) was used to investigate real time adhesion and stiffness of living VSMCs. A proprietary software package written in Matlab was used to estimate Young’s modulus of the cell cortex. Cell adhesion was measured for 50-70% confluent cells with N-Cadherin coated stylus AFM probes on an AFM mounted on an inverted microscope. Our results suggested that fluvastatin and MβCD mediated cholesterol depletion increased N-cadherin mediated cell adhesion force by approx. 27% and 17% respectively. In addition, fluvastatin and MβCD respectively reduced VSMCs stiffness by approx. 24% and 29 % compared to control VSMCs. Altogether, the knowledge that we obtained in this project may lead to a novel therapeutic strategy that could potentially control and block VSMC migration and prevent atherosclerotic plaque formation by deciphering and regulating N-cadherin mediated adhesion

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TNF-α-mediated apoptosis in vascular smooth muscle cells requires p73

AJP Cell Physiology ◽

10.1152/ajpcell.00477.2004 ◽

2005 ◽

Vol 289 (1) ◽

pp. C199-C206 ◽

Cited By ~ 16

Author(s):

Vincent Tang ◽

Amy Dhirapong ◽

Annoel P. Yabes ◽

Robert H. Weiss

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Plaque Rupture ◽

Muscle Cells ◽

Western World ◽

Organ Systems ◽

Tnf Α ◽

Human Atheroma

Atherosclerosis, now considered an inflammatory process, is the leading cause of death in the Western world and is manifested by a variety of diseases in multiple organ systems. Because of its prevalence and associated morbidity, novel therapies directed at arresting this progressive process are urgently needed. The inflammatory mediator TNF-α, which is known to contribute to apoptosis in vascular smooth muscle cells, has been shown to be intimately involved in the atherosclerotic process, being present at elevated levels in human atheroma as well as possibly being responsible for plaque rupture, a clinically devastating event. In light of our earlier finding that p73 is a proapoptotic protein in vascular smooth muscle cells, which are involved in plaque progression as well as rupture, we asked whether TNF-α mediates apoptosis in these cells through p73. We now show that p73 is present in spindle-shaped cells within human atheroma, and p73β, an isoform that is pivotal in both apoptosis and growth suppression, is induced in vascular smooth muscle cells in vitro by serum but not by PDGF-BB. In addition, TNF-α, when added to these cells in the presence of serum-containing media, increases p73β expression and causes apoptosis in both rat and human vascular smooth muscle cells. Inhibition of p73 activity with a dominant inhibitory NH2-terminally deleted p73 plasmid results in markedly decreased TNF-α-induced apoptosis. Thus p73β is likely a mediator of the apoptotic effect of TNF-α in the vasculature, such that future targeting of the p73 isoforms may ultimately prove useful in novel atherosclerosis therapies.

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