Lipid Regulators during Atherogenesis: Expression of LXR, PPAR, and SREBP mRNA in the Human Aorta

Shchelkunova, T. A.; Морозов, И. А.; Rubtsov, P. M.; Bobryshev, Yuri V.; Sobenin, Igor A.; Orekhov, Alexander N.; Андрианова, И. В.; Смирнов, А. Н.

doi:10.1371/journal.pone.0063374

Cited by 17 publications

(10 citation statements)

References 24 publications

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“…Meanwhile, PPARs can also repress gene expression by antagonizing the activities of NF-κB and activator proteins [ 46 ]. Our results also demonstrated that PPAR gene expression and protein levels were both up-regulated in AS lesions of the abdominal aorta, which is consistent with the results of previous clinical studies by Shchelkunova et al [ 52 ]. Additionally, NF-κB protein and levels of its downstream inflammatory factors, such as IL-1β, TNF-α, ICAM-1, VCAM-1, MCP-1, MMP-9, and CRP were also increased in HFC-fed minipigs (Figure 8 ).…”

Section: Discussionsupporting

confidence: 93%

Involvement of peroxisome proliferator-activated receptors in cardiac and vascular remodeling in a novel minipig model of insulin resistance and atherosclerosis induced by consumption of a high-fat/cholesterol diet

Pan

Cai

et al. 2015

Cardiovasc Diabetol

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BackgroundA long-term high-fat/cholesterol (HFC) diet leads to insulin resistance (IR), which is associated with inflammation, atherosclerosis (AS), cardiac sympathovagal imbalance, and cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) and nuclear factor ĸB (NF-κB) are involved in the development of IR-AS. Thus, we elucidated the pathological molecular mechanism of IR-AS by feeding an HFC diet to Tibetan minipigs to induce IR and AS.MethodsMale Tibetan minipigs were fed either a normal diet or an HFC diet for 24 weeks. Thereafter, the minipigs were tested for physiological and biochemical blood indices, blood pressure, cardiac function, glucose tolerance, heart rate variability (HRV), and PPAR-associated gene and protein expression levels.ResultsHFC-fed minipigs exhibited IR through increased body weight, fasting blood glucose levels, plasma cholesterol and its composition, and insulin and free fatty acid (FFA) levels; decreased insulin sensitivity; impaired glucose tolerance; and hypertension. Increased C-reactive protein (CRP) levels, cardiac dysfunction, depressed HRV, and the up-regulation of PPAR expression in the abdominal aorta concomitant with down-regulation in the heart tissue were observed in HFC-fed minipigs. Furthermore, the levels of NF-κBp65, IL-1β, TNF-α, MCP-1, VCAM-1, ICAM-1, MMP-9, and CRP proteins were also significantly increased.ConclusionsThese data suggest that HFC-fed Tibetan minipigs develop IR and AS and that PPARs are involved in cardiovascular remodeling and impaired function.

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Section: Discussionsupporting

confidence: 93%

Involvement of peroxisome proliferator-activated receptors in cardiac and vascular remodeling in a novel minipig model of insulin resistance and atherosclerosis induced by consumption of a high-fat/cholesterol diet

Pan

Cai

et al. 2015

Cardiovasc Diabetol

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“…In BMDMs, DGAT2 mRNA levels were significantly decreased, while SREBP1 levels were significantly upregulated. A previous study investigating the effects of cholesterol loading on expression of lipid metabolism genes in human monocyte derived macrophages, also detected decreased SREBP2 expression upon lipid loading 28 , thus mimicking the results obtained in PEMs in our study. This study also analysed mRNA expression of selected lipid metabolism genes in vivo (in human atherosclerotic lesions vs normal artery) and concluded, amongst others, that there was only partial similarity between changes in expression levels of lipid metabolism genes during plaque progression in vivo and lipid loading in vitro 28 .…”

Section: Discussionsupporting

confidence: 90%

“…A previous study investigating the effects of cholesterol loading on expression of lipid metabolism genes in human monocyte derived macrophages, also detected decreased SREBP2 expression upon lipid loading 28 , thus mimicking the results obtained in PEMs in our study. This study also analysed mRNA expression of selected lipid metabolism genes in vivo (in human atherosclerotic lesions vs normal artery) and concluded, amongst others, that there was only partial similarity between changes in expression levels of lipid metabolism genes during plaque progression in vivo and lipid loading in vitro 28 . Although the 2 studies are difficult to compare directly, since there are differences in both the study setup, and the genes analysed, the fact that both studies only detect partial similarity of findings in vivo and in vitro highlights the difficulty in comparing, and trying to decipher, in vivo pathological pathways using in vitro model systems.…”

Section: Discussionsupporting

confidence: 90%

Bone marrow-derived and peritoneal macrophages have different inflammatory response to oxLDL and M1/M2 marker expression – implications for atherosclerosis research

Bisgaard

Mogensen

Rosendahl

et al. 2016

Sci Rep

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Macrophages are heterogeneous and can polarize into specific subsets, e.g. pro-inflammatory M1-like and re-modelling M2-like macrophages. To determine if peritoneal macrophages (PEMs) or bone marrow derived macrophages (BMDMs) resembled aortic macrophages from ApoE−/− mice, their M1/M2 phenotype, inflammatory status, and lipid metabolism signatures were compared. oxLDL accumulation was similar in PEMs and BMDMs. On protein expression level, BMDMs showed an M2-like CD206highCD11clow profile, while cholesterol loading led to enhanced CD11c expression and reduced MCP-1 secretion. In contrast, PEMs expressed low levels of CD206 and CD11c, and responded to cholesterol loading by increasing CD11c expression and MCP-1 secretion. mRNA expression of M1/M2 markers was higher in PEMS than BMDMs, while lipid metabolism genes were similarly expressed. Whole aorta flow cytometry showed an accumulation of M2-like CD206highCD11clow macrophages in advanced versus early atherosclerotic disease in ApoE−/− mice. In isolated lesions, mRNA levels of the M2 markers Socs2, CD206, Retnla, and IL4 were downregulated with increasing disease severity. Likewise, mRNA expression of lipid metabolism genes (SREBP2, ACSL1, SRB1, DGAT1, and cpt1a) was decreased in advanced versus early lesions. In conclusion, PEMs and BMDMs are phenotypically distinct and differ from macrophages in lesions with respect to expression of M1/M2 markers and lipid metabolism genes.

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“…Results showed that SREBF2 mRNA was found comparable to non-diseased tissue in initial lesions. Otherwise SREBF2 transcript was found to be progressively up-regulated in fatty streaks and fibrous lipid plaques, supporting an active role of this biomolecule during the atherosclerosis progression [46]. The present study shows an association between the circulating expression levels of SREBF2 mRNA in PBMNCs and the presence of obstructive CHD.…”

Section: Discussionsupporting

confidence: 74%

Evidence of association of circulating epigenetic-sensitive biomarkers with suspected coronary heart disease evaluated by Cardiac Computed Tomography

et al. 2019

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Circulating biomarkers available in clinical practice do not allow to stratify patients with coronary heart disease (CHD) prior the onset of a clinically relevant event. We evaluated the methylation status of specific genomic segments and gene expression in peripheral blood of patients undergoing Cardiac Computed Tomography (CCT) for CHD (n = 95).We choose to investigate cholesterol metabolism. Methylation and gene expression of low density lipoprotein receptor (LDLR), sterol regulatory element-binding factor 2 (SREBF2) and ATP-binding cassette transporter 1 (ABCA1) were evaluated by qRT-PCR. Calcium score (CACS), stenosis degree, total plaque volume (TPV), calcified plaque volume (CPV), non-calcified plaque volume (NCPV) and plaque burden (PB) were assessed in all CHD patients (n = 65). The percentage of methylation at the specific analyzed segment of LDLR promoter was higher in CHD patients vs healthy subjects (HS) (n = 30) (p = 0.001). LDLR, SREBF2 and ABCA1 mRNAs were up-regulated in CHD patients vs HS (p = 0.02; p = 0.019; p = 0.008). SREBF2 was overexpressed in patients with coronary stenosis ≥50% vs subjects with stenosis <50% (p = 0.036). After adjustment for risk factors and clinical features, ABCA1 (p = 0.005) and SREBF2 (p = 0.010) gene expression were identified as independent predictors of CHD and severity. ROC curve analysis revealed a good performance of ABCA1 on predicting CHD (AUC = 0.768; p<0.001) and of SREBF2 for the prediction of disease severity (AUC = 0.815; p<0.001). Moreover, adjusted multivariate analysis demonstrated SREBF2 as independent predictor of CPV, NCPV and TPV (p = 0.022; p = 0.002 and p = 0.006) and ABCA1 as independent predictor of NCPV and TPV (p = 0.002 and p = 0.013).CHD presence and characteristics are related to selected circulating transcriptional and epigenetic-sensitive biomarkers linked to cholesterol pathway. More extensive analysis of CHD phenotypes and circulating biomarkers might improve and personalize cardiovascular risk stratification in the clinical settings.

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Lipid Regulators during Atherogenesis: Expression of LXR, PPAR, and SREBP mRNA in the Human Aorta

Cited by 17 publications

References 24 publications

Involvement of peroxisome proliferator-activated receptors in cardiac and vascular remodeling in a novel minipig model of insulin resistance and atherosclerosis induced by consumption of a high-fat/cholesterol diet

Involvement of peroxisome proliferator-activated receptors in cardiac and vascular remodeling in a novel minipig model of insulin resistance and atherosclerosis induced by consumption of a high-fat/cholesterol diet

Bone marrow-derived and peritoneal macrophages have different inflammatory response to oxLDL and M1/M2 marker expression – implications for atherosclerosis research

Evidence of association of circulating epigenetic-sensitive biomarkers with suspected coronary heart disease evaluated by Cardiac Computed Tomography

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