Abstract 1952: ABCA1 Deficency Diminishes Dysfunctional HDL And Inhibits Early Atherosclerotic Lesion Development In SR-BI Knockout Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ying Zhao ◽  
Ruud Out ◽  
Dan Ye ◽  
Theo J Van Berkel ◽  
Miranda Van Eck
Keyword(s):  
Serum Cholesterol ◽  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
Lesion Development ◽  
Cholesterol Levels ◽  
Total Body ◽  
Early Atherosclerotic Lesion ◽  
Atherosclerotic Lesion Development

Objective: ABCA1 and SR-BI play an essential role in reverse cholesterol transport (RCT) from macrophages in the arterial wall to the liver. The aim of this study was to investigate the effect of combined total-body ABCA1 and SR-BI deficiency on lipoprotein metabolism and atherosclerosis. Methods & Results: ABCA1/SR-BI double knockout (dKO), ABCA1 KO (AKO), SR-BI KO (SKO), and wildtype (WT) littermates were fed an atherogenic diet for 10 weeks to induce atherosclerosis. Under these conditions, SR-BI deficiency leads to largely increased serum cholesterol (C) levels (SKO: 470±68 mg/dL vs WT: 181±9 mg/dL, p<0.001), due to an impaired removal of HDL-C and VLDL-C, while hampered HDL production in AKO mice resulted in cholesterol levels of only 23±4 mg/dL (p<0.0001). In dKO mice, HDL-C was similarly low as in single AKO mice. Total serum cholesterol levels, however, were 3.8-fold (p<0.001) higher, due to increased VLDL-C levels. Interestingly, more extreme foam cell accumulation was observed in the peritoneal cavity of dKO mice ((30±6%, p<0.01), as compared to WT (1.7±0.2%), SKO (2.5±0.3%), and AKO (5±2%) mice. Combined deletion of ABCA1 and SR-BI thus induces macrophage foam cell formation in vivo . The accumulation of HDL-C and VLDL-C in SKO mice dramatically induced atherosclerotic lesion formation (206±16x10 3 μm 2 vs 12±2x10 3 μm 2 for WT mice, p<0.001)), while lesions were only 33±12x10 3 μm 2 (p<0.05) in AKO and 51±19x10 3 μm 2 (p<0.01) in dKO mice with low HDL-C levels. Thus, despite enhanced foam cell formation in dKO mice, ABCA1 deletion reduces the atherosclerosis susceptibility of SKO mice. Next, the serum atherogenicity was tested by incubation of RAM cells with 3% serum of different types of mice. Serum from SKO mice induced more extreme foam cell formation (89±2%, p<0.001), compared to serum from WT (31±3%), AKO (2.3±0.1%), and dKO (3.1±0.5%) mice. Interestingly, this effect highly correlated with both HDL-C (r=0.98, p<0.0001) and VLDL/LDL-C levels (r=0.96, p<0.0001). Conclusion: Total-body ABCA1 deficiency inhibits early atherosclerotic lesion development in SR-BI KO mice, which might be attributable to reduced circulating levels of pro-atherogenic HDL. Furthermore, both SR-BI and ABCA1 are essential for maintaining HDL-mediated RCT.

scholarly journals Signal Transducer and Activator of Transcription 1 Is Required for Optimal Foam Cell Formation and Atherosclerotic Lesion Development

Circulation ◽  
2007 ◽  
Vol 115 (23) ◽  
pp. 2939-2947 ◽  
Author(s):  
Sudesh Agrawal ◽  
Maria Febbraio ◽  
Eugene Podrez ◽  
Martha K. Cathcart ◽  
George R. Stark ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
Signal Transducer ◽  
Lesion Development ◽  
Atherosclerotic Lesion Development

scholarly journals Smooth Muscle Cell-Proteoglycan-Lipoprotein Interactions as Drivers of Atherosclerosis

2020 ◽  
Author(s):  
Sima Allahverdian ◽  
Carleena Ortega ◽  
Gordon A. Francis
Keyword(s):  
Smooth Muscle ◽  
Foam Cell ◽  
Current Knowledge ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
Lesion Development ◽  
Main Cell Type ◽  
Atherosclerosis Prevention ◽  
Atherosclerotic Lesion Development

AbstractIn humans, smooth muscle cells (SMCs) are the main cell type in the artery medial layer, in pre-atherosclerotic diffuse thickening of the intima, and in all stages of atherosclerotic lesion development. SMCs secrete the proteoglycans responsible for the initial binding and retention of atherogenic lipoproteins in the artery intima, with this retention driving foam cell formation and subsequent stages of atherosclerosis. In this chapter we review current knowledge of the extracellular matrix generated by SMCs in medial and intimal arterial layers, their relationship to atherosclerotic lesion development and stabilization, how these findings correlate with mouse models of atherosclerosis, and potential therapies aimed at targeting the SMC matrix-lipoprotein interaction for atherosclerosis prevention.

Dynamic Role of Macrophage Sub Types for Development of Atherosclerosis and Potential Use of Herbal Immunomodulators as Imminent Therapeutic Strategy

2020 ◽  
Vol 18 ◽  
Author(s):  
Parimalanandhini Duraisamy ◽  
Sangeetha Ravi ◽  
Mahalakshmi Krishnan ◽  
Catherene M. Livya ◽  
Beulaja Manikandan ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
Atherosclerosis Progression ◽  
Proinflammatory Mediators ◽  
M1 Macrophage ◽  
Tnf Α ◽  
Inflammatory Site

: Atherosclerosis, a major contributor to cardiovascular disease is a global alarm causing mortality worldwide. Being a progressive disease in the arteries, it mainly causes recruitment of monocytes to the inflammatory sites and subside pathological conditions. Monocyte-derived macrophage mainly acts in foam cell formation by engorging the LDL molecules, oxidizes it into Ox-LDL and leads to plaque deposit development. Macrophages in general differentiate, proliferate and undergo apoptosis at the inflammatory site. Frequently two subtypes of macrophages M1 and M2 has to act crucially in balancing the micro-environmental conditions of endothelial cells in arteries. The productions of proinflammatory mediators like IL-1, IL-6, TNF-α by M1 macrophage has atherogenic properties majorly produced during the early progression of atherosclerotic plaques. To counteract cytokine productions and M1-M2 balance, secondary metabolites (phytochemicals) from plants act as a therapeutic agent in alleviating atherosclerosis progression. This review summarizes the fundamental role of the macrophage in atherosclerotic lesion formation along with its plasticity characteristic as well as recent therapeutic strategies using herbal components and anti-inflammatory cytokines as potential immunomodulators.

Abstract 57: The Epigenetic Enzyme Kdm6b Controls the Pro-Fibrotic Transcriptome Signature of Foam Cells

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Annette E Neele ◽  
Koen H Prange ◽  
Marten A Hoeksema ◽  
Saskia van der Velden ◽  
Tina Lucas ◽  
...  
Keyword(s):  
Foam Cell ◽  
Smooth Muscle Actin ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Cell Phenotype ◽  
Sequencing Analysis ◽  
Dependent Manner ◽  
Alpha Smooth Muscle Actin

Aim: Foam cells are a key hallmark of atherosclerotic lesion formation. Within the atherosclerotic lesion macrophages scavenge modified lipoproteins and thereby acquire their foam cell characteristics. Besides their foam cell phenotype, macrophages can have specific inflammation regulatory functions in atherosclerotic lesions. Epigenetic pathways are crucial for monocyte to macrophage differentiation and activation. The H3K27 demethylase Kdm6b (also known as Jmjd3) is regulated in response to various triggers and regulates several modes of macrophage activation. Given the crucial role of macrophage foam cells in atherosclerosis, we here studied Kdm6b in peritoneal foam cells in order to identify regulated pathways. Material and Methods: A myeloid deficient Kdm6b mice (LysMCre-Kdm6b fl/fl ) was generated and bone marrow of Kdm6b wt or Kdm6b del mice was transplanted to irradiated Ldlr -/- mice which were fed a high fat diet for 9 weeks to induce foam cell formation. Peritoneal foam cells from Kdm6b del or Kdm6b wt mice were isolated and used for RNA-sequencing analysis. Results: Among the list of downregulated genes many genes involving fibrosis were affected in Kdm6b deficient foam cells including Collagen genes ( Col1a1 , Col1a2 ), Alpha smooth muscle actin ( Acta2 ) and Fibronectin-1 ( Fn1 ). Pathway analysis on downregulated genes ( P -value < 0.05) indicated that pathways involved in epithelial to mesenchymaltransition (EMT) ( q- value=10 -13 ) and extracellular matrix organization ( q- value=10 -4 ) were significantly downregulated. Pro-fibrotic pathways were thus strongly suppressed in Kdm6b deleted foam cells. Analysis of published datasets of foam cells showed that foam cell formation induces these pro-fibrotic characteristics. Overlay of both data sets indicated that fibrotic genes which are induced upon foam cell formation, are reduced in the absence of Kdm6b. These data suggest that foam cell formation induces a pro-fibrotic gene signature in a Kdm6b-dependent manner. Conclusion: We identified Kdm6b as a novel regulator of the pro-fibrotic signature of peritoneal foam cells.

Differentiation factors and cytokines in the atherosclerotic plaque micro-environment as a trigger for macrophage polarisation

2011 ◽  
Vol 106 (11) ◽  
pp. 763-771 ◽  
Author(s):  
Ine Wolfs ◽  
Marjo Donners ◽  
Menno de Winther
Keyword(s):  
Inflammatory Cell ◽  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
M1 Macrophages ◽  
Macrophage Polarisation ◽  
Atherosclerotic Lesions ◽  
Differentiation Factors

SummaryThe phenotype of macrophages in atherosclerotic lesions can vary dramatically, from a large lipid laden foam cell to a small inflammatory cell. Classically, the concept of macrophage heterogeneity discriminates between two extremes called either pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. Polarisation of plaque macrophages is predominantly determined by the local micro-environment present in the atherosclerotic lesion and is rather more complex than typically described by the M1/M2 paradigm. In this review we will discuss the role of various polarising factors in regulating the phenotypical state of plaque macrophages. We will focus on two main levels of phenotype regulation, one determined by differentiation factors produced in the lesion and the other determined by T-cell-derived polarising cytokines. With foam cell formation being a key characteristic of macrophages during atherosclerosis initiation and progression, these polarisation factors will also be linked to lipid handling of macrophages.

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