The P2RY12 receptor promotes VSMC-derived foam cell formation by inhibiting autophagy in advanced atherosclerosis

Pi, Shulan; Mao, Ling; Chen, Jiefang; Shi, Hanqing; Liu, Yu-Xiao; Guo, Xiaoqing; Li, Yuanyuan; Zhou, Lian; He, Hui; Yu, Cheng; Liu, Jianyong; Dang, Yiping; Xia, Yuanpeng; He, Quanwei; Jin, Huijuan; Li, Yanan; Hu, Yu; Miao, Yi‐Liang; Yue, Zhenyu; Hu, Bo

doi:10.1080/15548627.2020.1741202

Cited by 130 publications

(73 citation statements)

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“…51 No direct links between P2RY12 and PD have been reported in the literature, but P2RY12 is a widely studied gene with roles suggested in neuroinflammation, apoptosis, and autophagy, pathways that are relevant to PD and other neurodegenerative diseases. [52][53][54] Experiments have been done to characterize expression patterns of P2RY12 in microglia and its role in neuroinflammation. 55 As these experiments focused on Alzheimer's disease, it would be useful to build on them in the PD context in the future.…”

Section: Use Case Scenario 1 Locus 16 Rs11707416mentioning

confidence: 99%

The Parkinson's Disease Genome‐Wide Association Study Locus Browser

et al. 2020

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Background Parkinson's disease (PD) is a neurodegenerative disease with an often complex component identifiable by genome‐wide association studies. The most recent large‐scale PD genome‐wide association studies have identified more than 90 independent risk variants for PD risk and progression across more than 80 genomic regions. One major challenge in current genomics is the identification of the causal gene(s) and variant(s) at each genome‐wide association study locus. The objective of the current study was to create a tool that would display data for relevant PD risk loci and provide guidance with the prioritization of causal genes and potential mechanisms at each locus. Methods We included all significant genome‐wide signals from multiple recent PD genome‐wide association studies including themost recent PD risk genome‐wide association study, age‐at‐onset genome‐wide association study, progression genome‐wide association study, and Asian population PD risk genome‐wide association study. We gathered data for all genes 1 Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self‐ranked criteria. Multiple databases were queried for each gene to collect additional causal data. Results We created a PD genome‐wide association study browser tool ( https://pdgenetics.shinyapps.io/GWASBrowser/ ) to assist the PD research community with the prioritization of genes for follow‐up functional studies to identify potential therapeutic targets. Conclusions Our PD genome‐wide association study browser tool provides users with a useful method of identifying potential causal genes at all known PD risk loci from large‐scale PD genome‐wide association studies. We plan to update this tool with new relevant data as sample sizes increase and new PD risk loci are discovered. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

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Section: Use Case Scenario 1 Locus 16 Rs11707416mentioning

confidence: 99%

The Parkinson's Disease Genome‐Wide Association Study Locus Browser

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“…As a catalytic subunit, mTOR can integrate various physiological stimuli to regulate the growth and metabolism of cells. The PI3K/Akt/mTOR signaling pathway is thought to be a crucial regulator of autophagy and apoptosis [55,56]. It has been con rmed that the mechanisms of apoptosis and autophagy in vascular smooth muscle cells were involved in vascular remodeling of hypertension [57].…”

Section: Discussionmentioning

confidence: 99%

Comparative Transcriptomic Analysis Revealed Novel Potential Therapeutic Targets Of Traditional Chinese Medicine (Pinggan-Qianyang Decoction) On Vascular Remodeling In Spontaneously Hypertensive Rats

Yao

Zhang

Yang

et al. 2020

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Background: Both experimental and clinical studies have revealed satisfactory effects with the traditional Chinese formula Pinggan Qianyang decoction (PGQYD) for improving vascular remodeling caused by essential hypertension. The present study explored various therapeutic targets of PGQYD using mRNA transcriptomics. Methods: In this study, rats were randomly divided into three groups: Wistar-Kyoto (WKY; normal control), spontaneously hypertensive (SHR), and PGQYD-treated rat groups. After 12 weeks of PGQYD treatment, behavioral tests were employed and the morphology of thoracic aortas were examined with hematoxylin-eosin (HE) and Masson staining and electron microscopy. The mRNA expression profiles were identified with RNA-Seq and quantitative real-time PCR to validate changes in gene expression observed with microarray analysis. The gene ontology and pathway enrichment analyses were carried out to predict gene function and gene co-expressions. Pathway networks were constructed to identify the hub biomarkers, which were further validated by western blotting and immunofluorescence analysis. Results: After PGQYD treatment, the behavioral tests and histological and morphological findings of vascular remodeling were obviously meliorated compared with the SHR group. In the rat thoracic aorta tissues, 626 mRNAs with an exact match were identified. A total of 129 of mRNAs (fold change >1.3 and P-value <0.05) were significantly changed in the SHR group compared to the WKY group. Among them, 16 mRNAs were markedly regulated by PGQYD treatment and validated with quantitative real-time PCR. Additionally, target prediction and bioinformatics analyses revealed that these mRNAs could play therapeutic roles through biological processes for regulating cell metabolic processes (such as glycation biology), biological adhesions, rhythmic processes, and cell aggregation. The cellular signaling pathways involved in glycosylation may be AGE-RAGE signaling pathway.Conclusion: The present study provides novel insights for future investigations to explore the mechanisms by which PGQYD may effectively inhibit vascular remodeling by activating the AGE-RAGE signal pathway in glycation biology.

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“…There was evidence demonstrating that autophagy activities were capable of weakening the extent of atheroma plaques via promoting cholesterol e ux of macrophages and then prohibiting foam cell formation [15,41,42]. Besides, autophagy was reported to modulate the polarization conversion of macrophage phenotype [43].…”

Section: Discussionmentioning

confidence: 99%

Rosuvastatin Inhibits Atherosclerosis Development by Improving Lipid Accumulation and Polarization Conversion of Macrophages via Regulating Autophagy

Zhang¹,

Qin²,

Wan³

et al. 2020

Preprint

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Background Atherosclerosis is a chronic vascular disease posing a great threat to public health. We investigated whether rosuvastatin (RVS) enhanced autophagic activities to inhibit lipid accumulation and polarization conversion of macrophages and then attenuate atherosclerotic lesions. Methods All male Apolipoprotein E-deficient (ApoE-/-) mice were fed high-fat diet supplemented with RVS (10mg/kg/day) or the same volume of normal saline gavage for 20 weeks. The burden of plaques in mice were determined by histopathological staining. Biochemical kits were used to examine the levels of lipid profiles and inflammatory cytokines. The potential mechanisms by which RVS mediated atherosclerosis were explored by western blot, real-time PCR assay, and immunofluorescence staining in mice and RAW264.7 macrophages.Results Our data showed that RVS treatment reduced plaque areas in the aorta inner surface and the aortic sinus of ApoE-/- mice with high-fat diet. RVS markedly improved lipid profiles and reduced contents of inflammatory cytokines in the circulation. Then, results of Western blot showed that RVS increased the ratio LC3II/I and level of Beclin 1 and decreased the expression of p62 in aortic tissues, which might be attributed to suppression of PI3K/Akt/mTOR pathway, hinting that autophagy cascades were activated by RVS. Moreover, RVS raised the contents of ABCA1, ABCG1, Arg-1, CD206 and reduced iNOS expression of arterial wall, indicating that RVS promoted cholesterol efflux and M2 macrophage polarization. Similarly, we observed that RVS decreased lipids contents and inflammatory factors expressions in RAW264.7 cells stimulated by ox-LDL, accompanied by levels elevation of ABCA1, ABCG1, Arg-1, CD206 and content reduction of iNOS. These anti-atherosclerotic effects of RVS were abolished by 3-methyladenine intervention. Moreover, RVS could reverse the impaired autophagy flux in macrophages insulted by chloroquine. We further found that PI3K inhibitor LY294002 enhanced and agonist 740 Y-P weakened the autophagy-promoting roles of RVS, respectively. Conclusions Our study indicated that RVS exhibits atheroprotective effects involving regulation lipid accumulation and polarization conversion by improving autophagy initiation and development via suppressing PI3K/Akt/mTOR axis and enhancing autophagic flux in macrophages.

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The P2RY12 receptor promotes VSMC-derived foam cell formation by inhibiting autophagy in advanced atherosclerosis

Cited by 130 publications

References 59 publications

The Parkinson's Disease Genome‐Wide Association Study Locus Browser

The Parkinson's Disease Genome‐Wide Association Study Locus Browser

Comparative Transcriptomic Analysis Revealed Novel Potential Therapeutic Targets Of Traditional Chinese Medicine (Pinggan-Qianyang Decoction) On Vascular Remodeling In Spontaneously Hypertensive Rats

Rosuvastatin Inhibits Atherosclerosis Development by Improving Lipid Accumulation and Polarization Conversion of Macrophages via Regulating Autophagy

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