Abstract 436: Smooth Muscle Specific Knock-out of the Zinc-Finger Protein 148(ZFP148) Attenuates Atherosclerotic Lesion Formation via Regulation of Apoptotic Signaling Pathways

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Morgan Salmon ◽  
Anna Z Fashandi ◽  
Michael D Spinosa ◽  
Ashish K Sharma ◽  
Gary K Owens ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Zinc Finger Protein ◽  
Atherosclerotic Lesion ◽  
Muscle Cells ◽  
Lesion Size ◽  
Western Diet ◽  
Lesion Formation ◽  
Knock Out ◽  
Atherosclerotic Lesion Formation

Objective: Zinc-finger protein 148 (ZFP148) plays a profound role in the modulation of aortic aneurysm formation in part via modulation of smooth muscle (SMC) genes. The current study objective was to determine whether smooth muscle specific knock-out of ZFP148 is critical in atherosclerotic lesion formation. Methods: ZFP148 was examined via immunohistochemistry and confocal microscopy in human atherosclerotic lesion samples (n=12/group). 6-8 week male (n=12/group) ZFP flx/flx Myh11 Cre+ ApoE-/-(SMC tamoxifen ZFP148 KO), Myh11 ZFP148 flx/wt Cre+ ApoE-/- and Myh11 ZFP wt/wt Cre+ ApoE-/- underwent tamoxifen injections followed by western diet feeding for either 13 or 25 weeks. A separate set of mice were fed western diet for 18 weeks and then administered tamoxifen injections. Aortic samples were evaluated with histology for α-actin, macrophages, neutrophils, TER119, caspase3, Ki67, picosirus red and movat staining. In vitro ZFP148 was knocked down using siRNA in smooth muscle cells and stimulated with the oxidized phospholipid POVPC. Results: ZFP148 expression was elevated in human atherosclerotic lesion samples and localized to smooth muscle cells. Lesion size was significantly reduced in SMC ZFP148 KO mice compared with controls in 25 week western diet fed mice(p<0.0357). SMC ZFP148 KO demonstrated reduced macrophage, Caspase3, and TER119 staining. Conversely, SMC ZFP148 KO increased SMα-actin coverage. Lesion size was also decreased in mice that were administered tamoxifen injections following 18 weeks of western diet feeding(p<0.0415). There were no significant changes in lesion size at 13 weeks of western diet feeding; however, macrophage staining was decreased. Knock-down of ZFP148 followed by treatment with POVPC attenuated the down-regulation of SM22α, SM-MHC, and SMαA. Knock-down of ZFP148 followed by POVPC treatment also prevented the up-regulation of Bax and BAD in vascular smooth muscle cells. Conclusions: While earlier studies documented a role for ZFP148 in aneurysm disease, the present study suggests that SMC ZFP148 KO attenuates atherosclerotic lesion formation in early and late atherosclerotic disease. ZFP148 represents a key regulator of multiple types of vascular disease.

scholarly journals Runx2 deletion in smooth muscle cells inhibits vascular osteochondrogenesis and calcification but not atherosclerotic lesion formation

2016 ◽  
Vol 112 (2) ◽  
pp. 606-616 ◽  
Author(s):  
Mu-En Lin ◽  
Theodore M. Chen ◽  
Mary C. Wallingford ◽  
Ngoc B. Nguyen ◽  
Shunsuke Yamada ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Atherosclerotic Lesion ◽  
Muscle Cells ◽  
Lesion Formation ◽  
Atherosclerotic Lesion Formation

Abstract 238: ABCA1 and HDL3 are Required to Modulate Smooth Muscle Cells Trandifferentiation in a Myocardin-miR143/145-dependent Process

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Silvia Castiglioni ◽  
Alessio Vettore ◽  
Lorenzo Arnaboldi ◽  
Laura Calabresi ◽  
Alberto Corsini ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Cell Types ◽  
Foam Cells ◽  
Knock Out ◽  
Phenotypic Changes ◽  
Basal Expression ◽  
Basal Expression Level

Cells of the artery wall may accumulate free cholesterol and cholesteryl esters becoming foam cells. Up to 50% of foam cells in human lesions originates from smooth muscle cells (SMCs). Arterial SMCs express the ATP binding cassette (ABC) transporter ABCA1 and, upon cholesterol loading, express macrophage markers and a phagocytic activity. To characterize the role of ABCA1 and HDL3 in this transdifferentiation process, we evaluated the phenotypic changes in SMCs isolated from wild type (WT) and ABCA1 knock out (KO) mice and how HDL3 affects these changes. Cholesterol loading causes the downregulation of the expression of SMC markers including ACTA2, alpha-tropomyosin and myosin heavy chain and increases the expression of macrophage-related genes such as CD68, Mac-2, SRB1, MMPs, ABCG1 and ABCA1. HDL3 treatment in WT cells is able to normalize the expression of ACTA2, while the expression of macrophage-related genes is reduced. On the contrary, the preventive effect of HDL3 is completely lost in ABCA1 KO cells. Interestingly, the presence of HDL3 does not differently affect neutral lipid accumulation in WT or ABCA1 KO cells but stimulates phospholipids removal only in WT cells. ApoAI addition does not reverse the phenotypic changes induced by cholesterol not only in KO but also in WT cells. Moreover, cholesterol loading reduces the expression of myocardin, the master SMC specific-transcriptional coactivator involved in SMC differentiation, by up to 55% (p<0.01 vs respective control) in both cell types. HDL3 normalizes myocardin levels in WT cells while it does not have any effect in ABCA1 KO cells. Similar results are obtained evaluating the levels of miR-143/145, which positively regulate myocardin. The basal expression level of KLF4, a myocardin repressor, is almost double in ABCA1 KO cells compared to WT. After cholesterol loading, KLF4 is slightly reduced in WT cells, while its expression is halved in ABCA1 KO cells. HDL3 restores KLF4 to basal levels in KO cells, but it further reduces them in WT cells. These results indicate that HDL3, modulating the miR143/145-myocardin axis in SMC, prevents the cholesterol-induced gene expression modification regardless of its cholesterol unloading capacity and the presence of ABCA1 is required.

scholarly journals Dominant negative PPARγ promotes atherosclerosis, vascular dysfunction, and hypertension through distinct effects in endothelium and vascular muscle

2013 ◽  
Vol 304 (9) ◽  
pp. R690-R701 ◽  
Author(s):  
Christopher J. Pelham ◽  
Henry L. Keen ◽  
Steven R. Lentz ◽  
Curt D. Sigmund
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Type Ii Diabetes ◽  
Atherosclerotic Lesion ◽  
Dominant Negative ◽  
Type Ii ◽  
Lesion Formation ◽  
Specific Expression ◽  
Altered Expression ◽  
Atherosclerotic Lesion Formation

Agonists of the nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) have potent insulin-sensitizing effects and inhibit atherosclerosis progression in patients with Type II diabetes. Conversely, missense mutations in the ligand-binding domain of PPARγ that render the transcription factor dominant negative (DN) cause early-onset hypertension and Type II diabetes. We tested the hypothesis that DN PPARγ-mediated interference of endogenous wild-type PPARγ in the endothelium and vascular smooth muscle exacerbates atherosclerosis in apolipoprotein E-deficient (ApoE−/−) mice. Endothelium-specific expression of DN PPARγ on the ApoE−/− background unmasked significant impairment of endothelium-dependent relaxation in aortic rings, increased systolic blood pressure, altered expression of atherogenic markers (e.g., Cd36, Mcp1, Catalase), and enhanced diet-induced atherosclerotic lesion formation in aorta. Smooth muscle-specific expression of DN PPARγ, which induces aortic dysfunction and increased systolic blood pressure at baseline, also resulted in enhanced diet-induced atherosclerotic lesion formation in aorta on the ApoE−/− background that was associated with altered expression of a shared, yet distinct, set of atherogenic markers (e.g., Cd36, Mcp1, Osteopontin, Vcam1). In particular, induction of Osteopontin expression by smooth muscle-specific DN PPARγ correlated with increased plaque calcification. These data demonstrate that inhibition of PPARγ function specifically in the vascular endothelium or smooth muscle may contribute to cardiovascular disease.

scholarly journals Influence of conjugated linoleic acids on functional properties of vascular cells

2009 ◽  
Vol 102 (8) ◽  
pp. 1099-1116 ◽  
Author(s):  
Robert Ringseis ◽  
Klaus Eder
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Functional Properties ◽  
Inflammatory Responses ◽  
Atherosclerotic Lesion ◽  
Muscle Cells ◽  
Vascular Wall ◽  
Mechanisms Of Action ◽  
Conjugated Linoleic Acids

Conjugated linoleic acids (CLA) are biologically highly active lipid compounds that inhibit the development of atherosclerotic plaques in experimental animals. The underlying mechanisms of action, however, are only poorly understood. Since cell-culture experiments are appropriate to provide a detailed view into the mechanisms of action of a compound, the present review summarises results from in vitro studies dealing with the effects of CLA isomers and CLA mixtures on functional properties of cells of the vascular wall, such as endothelial cells, smooth muscle cells and monocyte-derived macrophages, which are amongst the major cells contributing to atherosclerotic lesion development. Based on these studies, it can be concluded that CLA exert several beneficial actions in cells of the vascular wall through the activation of nuclear PPAR. These actions of CLA, which may, at least partially, explain the inhibition of atherogenesis by dietary CLA, include modulation of vasoactive mediator release from endothelial cells, inhibition of inflammatory and fibrotic processes in activated smooth muscle cells, abrogation of inflammatory responses in activated macrophages, and reduction of cholesterol accumulation in macrophage-derived foam cells.

scholarly journals The LIM-Only Protein FHL2 Reduces Vascular Lesion Formation Involving Inhibition of Proliferation and Migration of Smooth Muscle Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e94931 ◽  
Author(s):  
Kondababu Kurakula ◽  
Mariska Vos ◽  
Iker Otermin Rubio ◽  
Goran Marinković ◽  
Reinhard Buettner ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Vascular Lesion ◽  
Lesion Formation ◽  
Inhibition Of Proliferation ◽  
And Migration ◽  
Proliferation And Migration

scholarly journals SAMD1 Distribution Patterns in Mouse Atherosclerosis Models Suggest Roles in LDL Retention, Antigen Presentation, and Cell Phenotype Modulation

2021 ◽  
Author(s):  
Bruce Campbell ◽  
Patricia Bourassa ◽  
Robert Aiello
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Foam Cell ◽  
Ex Vivo ◽  
Muscle Cells ◽  
Distribution Patterns ◽  
Lesion Size ◽  
Cell Phenotype ◽  
Lesion Growth

The theory that lesions formed by retention of circulating LDL can then progress to complicated atherosclerotic lesions has been a subject of debate, as has the mechanism of retention. In earlier work, we identified SAMD1, a protein expressed by intimal smooth muscle cells in human lesions that appears to irreversibly bind apoB-Lps in extracellular matrix near the lumen. We hypothesized this binding could contribute to the formation of lesions in mice, and that inhibiting binding could reduce lesion growth. In mouse models of atherosclerosis, we found that SAMD1 binds LDL; that SAMD1/apoB complex is ingested by intimal cells; and that recognizable epitopes of the SAMD1/apoB complex survive some degree of catabolism in foam cell. These data appear to support the SAMD1/LDL retention hypothesis of lesion growth. Despite apparently irreversible binding of human LDL to full-length human SAMD1, efficient anti-SAMD1-antibody inhibitors were created. In vivo lesion targeting of inhibitors was demonstrated by MRI, ultrasound, and ex vivo microscopy. However, only non-statistically significant reductions in spontaneous lesion size in apoE-/- mice were seen after 12 weeks of treatment with PEG-fab inhibitors of SAMD1/LDL binding. In contrast, inhibitors substantially reduced LDL retention in carotid injury lesions in apoE-/- and LDLR-/- mice 7 days after injury. The most obvious difference between injury lesions and early spontaneous lesions is the presence of numerous SMCs and associated ECM in the injury lesions. Thus, SAMD1 may be involved in retention of apoB-Lps in mouse lesions, but not until smooth muscle cells have entered the intima. In addition, SAMD1 is seen throughout arteries in changing patterns that suggest broader and more complicated roles in atherosclerosis.

Smooth muscle cells PCSK9 knock-out exhibit an impaired response to PDGF stimulation

2016 ◽  
Vol 252 ◽  
pp. e200
Author(s):  
S. Marchianò ◽  
G. Tibolla ◽  
A. Corsini ◽  
A.L. Catapano ◽  
N. Ferri
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Knock Out ◽  
Pdgf Stimulation
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