scholarly journals Lipin-1 contributes to modified low-density lipoprotein-elicited macrophage pro-inflammatory responses

2015 ◽  
Vol 242 (2) ◽  
pp. 424-432 ◽  
Author(s):  
Aaron R. Navratil ◽  
Aimee E. Vozenilek ◽  
James A. Cardelli ◽  
Jonette M. Green ◽  
Michael J. Thomas ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipin 1

scholarly journals Deleting myeloid IL-10 receptor signalling attenuates atherosclerosis in LDLR-/- mice by altering intestinal cholesterol fluxes

2016 ◽  
Vol 116 (09) ◽  
pp. 565-577 ◽  
Author(s):  
Gemma Brufau ◽  
Marion J. J. Gijbels ◽  
Ine M. J. Wolfs ◽  
Saskia van der Velden ◽  
Chantal C. H. Pöttgens ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Homeostasis ◽  
Liver Cholesterol ◽  
Specific Cell ◽  
Low Density ◽  
Atherosclerosis Development ◽  
Deficient Mice

SummaryInflammatory responses and cholesterol homeostasis are interconnected in atherogenesis. Interleukin (IL)-10 is an important anti-inflammatory cytokine, known to suppress atherosclerosis development. However, the specific cell types responsible for the atheroprotective effects of IL-10 remain to be defined and knowledge on the actions of IL-10 in cholesterol homeostasis is scarce. Here we investigated the functional involvement of myeloid IL-10-mediated atheroprotection. To do so, bone marrow from IL-10 receptor 1 (IL-10R1) wild-type and myeloid IL-10R1-deficient mice was transplanted to lethally irradiated female LDLR-/- mice. Hereafter, mice were given a high cholesterol diet for 10 weeks after which atherosclerosis development and cholesterol metabolism were investigated. In vitro, myeloid IL-10R1 deficiency resulted in a pro-inflammatory macrophage phenotype. However, in vivo significantly reduced lesion size and severity was observed. This phenotype was associated with lower myeloid cell accumulation and more apoptosis in the lesions. Additionally, a profound reduction in plasma and liver cholesterol was observed upon myeloid IL-10R1 deficiency, which was reflected in plaque lipid content. This decreased hypercholesterolaemia was associated with lowered very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels, likely as a response to decreased intestinal cholesterol absorption. In addition, IL-10R1 deficient mice demonstrated substantially higher faecal sterol loss caused by increased non-biliary cholesterol efflux. The induction of this process was linked to impaired ACAT2-mediated esterification of liver and plasma cholesterol. Overall, myeloid cells do not contribute to IL-10-mediated atheroprotection. In addition, this study demonstrates a novel connection between IL-10-mediated inflammation and cholesterol homeostasis in atherosclerosis. These findings make us reconsider IL-10 as a beneficial influence on atherosclerosis.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Neutrophils as a Novel Target of Modified Low-Density Lipoproteins and an Accelerator of Cardiovascular Diseases

2020 ◽  
Vol 21 (21) ◽  
pp. 8312
Author(s):  
Takashi Obama ◽  
Hiroyuki Itabe
Keyword(s):  
Cardiovascular Diseases ◽  
Inflammatory Responses ◽  
Foam Cell ◽  
Vascular Endothelial Cells ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Oxidative Modification ◽  
Foam Cell Formation ◽  
Low Density

Neutrophil extracellular traps (NETs) significantly contribute to various pathophysiological conditions, including cardiovascular diseases. NET formation in the vasculature exhibits inflammatory and thrombogenic activities on the endothelium. NETs are induced by various stimulants such as exogenous damage-associated molecular patterns (DAMPs). Oxidatively modified low-density lipoprotein (oxLDL) has been physiologically defined as a subpopulation of LDL that comprises various oxidative modifications in the protein components and oxidized lipids, which could act as DAMPs. oxLDL has been recognized as a crucial initiator and accelerator of atherosclerosis through foam cell formation by macrophages; however, recent studies have demonstrated that oxLDL stimulates neutrophils to induce NET formation and enhance NET-mediated inflammatory responses in vascular endothelial cells, thereby suggesting that oxLDL may be involved in cardiovascular diseases through neutrophil activation. As NETs comprise myeloperoxidase and proteases, they have the potential to mediate oxidative modification of LDL. This review summarizes recent updates on the analysis of NETs, their implications for cardiovascular diseases, and prospects for a possible link between NET formation and oxidative modification of lipoproteins.

Cellular immunity, low-density lipoprotein and atherosclerosis: Break of tolerance in the artery wall

2011 ◽  
Vol 106 (11) ◽  
pp. 779-786 ◽  
Author(s):  
Daniel Ketelhuth ◽  
Göran Hansson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cellular Immunity ◽  
Inflammatory Responses ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Chronic Inflammatory Disease ◽  
Research Field ◽  
T Cell Subsets ◽  
Low Density

SummaryAtherosclerosis is a chronic inflammatory disease. Atherosclerotic plaques contain abundant immune cells that can dictate and effect inflammatory responses. Among them, T cells are present during all stages of the disease suggesting that they are essential in the initiation as well as the progression of plaque. Experimental as well as clinical research has demonstrated different T cell subsets, i.e. CD4+ Th1, Th2, Th17, and Treg as well as CD8+ and NKT cells in the plaque. Moreover, candidate antigens inducing T cell responses have been identified. Knowledge about the pathological role of these cells in atherogenesis may lead to development of new therapies. This review provides an overview of the research field of cellular immunity in atherosclerosis. It emphasises the events and findings involving antigen specific T cells, in particular low-density lipoprotein-specific T cells.

scholarly journals (Pro)renin Receptor Inhibition Reduces Plasma Cholesterol and Triglycerides but Does Not Attenuate Atherosclerosis in Atherosclerotic Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Dien Ye ◽  
Xiaofei Yang ◽  
Liwei Ren ◽  
Hong S. Lu ◽  
Yuan Sun ◽  
...  
Keyword(s):  
Plasma Lipids ◽  
Inflammatory Responses ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Low Density ◽  
Beneficial Effects ◽  
Receptor Inhibition ◽  
Density Lipoprotein Receptor

Objective: Elevated plasma cholesterol concentrations contributes to ischemic cardiovascular diseases. Recently, we showed that inhibiting hepatic (pro)renin receptor [(P)RR] attenuated diet-induced hypercholesterolemia and hypertriglyceridemia in low-density lipoprotein receptor (LDLR) deficient mice. The purpose of this study was to determine whether inhibiting hepatic (P)RR could attenuate atherosclerosis.Approach and Results: Eight-week-old male LDLR−/− mice were injected with either saline or N-acetylgalactosamine-modified antisense oligonucleotides (G-ASOs) primarily targeting hepatic (P)RR and were fed a western-type diet (WTD) for 16 weeks. (P)RR G-ASOs markedly reduced plasma cholesterol concentrations from 2,211 ± 146 to 1,128 ± 121 mg/dL. Fast protein liquid chromatography (FPLC) analyses revealed that cholesterol in very low-density lipoprotein (VLDL) and intermediate density lipoprotein (IDL)/LDL fraction were potently reduced by (P)RR G-ASOs. Moreover, (P)RR G-ASOs reduced plasma triglyceride concentrations by more than 80%. Strikingly, despite marked reduction in plasma lipid concentrations, atherosclerosis was not reduced but rather increased in these mice. Further testing in ApoE−/− mice confirmed that (P)RR G-ASOs reduced plasma lipid concentrations but not atherosclerosis. Transcriptomic analysis of the aortas revealed that (P)RR G-ASOs induced the expression of the genes involved in immune responses and inflammation. Further investigation revealed that (P)RR G-ASOs also inhibited (P)RR in macrophages and in enhanced inflammatory responses to exogenous stimuli. Moreover, deleting the (P)RR in macrophages resulted in accelerated atherosclerosis in WTD fed ApoE−/− mice.Conclusion: (P)RR G-ASOs reduced the plasma lipids in atherosclerotic mice due to hepatic (P)RR deficiency. However, augmented pro-inflammatory responses in macrophages due to (P)RR downregulation counteracted the beneficial effects of lowered plasma lipid concentrations on atherosclerosis. Our study demonstrated that hepatic (P)RR and macrophage (P)RR played a counteracting role in atherosclerosis.

Abstract P250: Sphingosine-1-phosphate Receptor Agonist And Very Low-density Lipoprotein Regulate Aldosterone Production Via Lipin-1 In Human Adrenocortical Cells

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Shinjini Chowdhury ◽  
Vivek Choudhary ◽  
Mrunal Choudhary ◽  
Xunsheng Chen ◽  
Wendy B Bollag
Keyword(s):  
Gene Expression ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Fold Increase ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Lipid Signal ◽  
Aldosterone Production ◽  
Sphingosine 1 Phosphate ◽  
Lipin 1

Aldosterone is considered to be a link between hypertension and obesity; obese individuals have high serum levels of both sphingosine-1-phosphate (S1P) and very low-density lipoprotein (VLDL). S1P has been reported to be a novel stimulator of aldosterone secretion and phospholipase D (PLD) activity. VLDL has also been shown to stimulate aldosterone production in multiple zona glomerulosa cell models via PLD. PLD is an enzyme that hydrolyzes phosphatidylcholine to phosphatidic acid (PA) which can then be converted to diacylglycerol (DAG) by lipin-1. However, it is unclear which of the two lipid signals, PA or DAG, underlies PLD’s mediation of aldosterone production. We hypothesized that the S1P1 receptor (S1PR1) agonist, SEW2871, (and VLDL) induces steroidogenesis and therefore aldosterone production via lipin-1-mediated metabolism of PA to DAG, with our hypothesis focusing on DAG as the key lipid signal produced by PLD (indirectly). In HAC15 cells, lipin-1 was overexpressed using an adenovirus or inhibited using propranolol followed by treatment with or without SEW2871 (or VLDL) for 24 h. Steroidogenic gene expression and aldosterone levels were monitored by qRT-PCR and radioimmunoassay, respectively. We demonstrated that lipin-1 overexpression (OE) enhanced the SEW2871-stimulated 109-fold increase in CYP11B2 expression by 26% while lipin-1 inhibition decreased the SEW2871-stimulated 56-fold increase in CYP11B2 expression by 74%. While lipin-1 OE had no further effect, propranolol reduced SEW2871-stimulated increases in NR4A1 (2-fold) and NR4A2 (9-fold) mRNA levels by 22% and 52% respectively. The SEW2871-stimulated increase in aldosterone production was inhibited by propranolol (53%), although it was not enhanced by lipin-1 OE. Similar results were obtained with VLDL. Our results are, therefore, suggestive of DAG being the key lipid signal since regulating lipin-1 affects S1PR1 agonist- and VLDL-stimulated steroidogenic gene expression and ultimately, aldosterone production. Our study warrants further investigation into these steroidogenic signaling pathways which can lead to the identification of novel therapeutic targets such as lipin-1, or its downstream pathways, to potentially treat obesity-associated hypertension.

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