Systems biology identifies cytosolic PLA2 as a target in vascular calcification treatment

Schanstra, Joost P.; Luong, Trang T. D.; Makridakis, Manousos; Linthout, Sophie Van; Lygirou, Vasiliki; Latosinska, Agnieszka; Alesutan, Ioana; Boehme, Beate; Schelski, Nadeshda; Lewinski, Dirk von; Mullen, William; Nicklin, Stuart A.; Delles, Christian; Feuillet, Guylène; Denis, Colette; Läng, Florian; Pieske, Burkert; Bascands, Jean-Loup; Mischak, Harald; Saulnier-Blache, Jean Sébastien; Voelkl, Jakob; Vlahou, Antonia; Klein, Julie

doi:10.1172/jci.insight.125638

Cited by 29 publications

(19 citation statements)

References 48 publications

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“…Sample preparation was performed as described in [ 12 , 13 , 14 ]. In brief, tissue samples (with net weight of 10–20 mg) were homogenized with a bullet blender homogenizer (Next Advance, Troy, NY, US) using stainless steel beads (0.9–2-mm diameter).…”

Section: Methodsmentioning

confidence: 99%

Molecular Changes in Tissue Proteome during Prostate Cancer Development: Proof-of-Principle Investigation

et al. 2020

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(1) Background: Prostate cancer (PCa) is characterized by high heterogeneity. The aim of this study was to investigate molecular alterations underlying PCa development based on proteomics data. (2) Methods: Liquid chromatography coupled to tandem mass spectrometry was conducted for 22 fresh-frozen tissue specimens from patients with benign prostatic hyperplasia (BPH, n = 5) and PCa (n = 17). Mann Whitney test was used to define significant differences between the two groups. Association of protein abundance with PCa progression was evaluated using Spearman correlation, followed by verification through investigating the Prostate Cancer Transcriptome Atlas. Functional enrichment and interactome analysis were carried out using Metascape and String. (3) Results: Proteomics analysis identified 1433 proteins, including 145 proteins as differentially abundant between patients with PCa and BPH. In silico analysis revealed alterations in several pathways and hallmarks implicated in metabolism and signalling, represented by 67 proteins. Among the latter, 21 proteins were correlated with PCa progression at both the protein and mRNA levels. Interactome analysis of these 21 proteins predicted interactions between Myc proto-oncogene (MYC) targets, protein processing in the endoplasmic reticulum, and oxidative phosphorylation, with MYC targets having a central role. (4) Conclusions: Tissue proteomics allowed for characterization of proteins and pathways consistently affected during PCa development. Further validation of these findings is required.

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Section: Methodsmentioning

confidence: 99%

Molecular Changes in Tissue Proteome during Prostate Cancer Development: Proof-of-Principle Investigation

et al. 2020

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“…while being rejected by CMap 1 (Zador et al, 2018). On the other hand, there are also anecdotal reports of positive results, in which researchers have experimentally verified the biological effects of candidate drugs recommended by CMap 1 (Braconi et al, 2009;Brum et al, 2015Brum et al, , 2018Byun et al, 2019;Johnstone et al, 2012;Luo et al, 2019;Schanstra et al, 2019;Wang et al, 2019;Wu et al, 2019) or CMap 2 (Ferguson et al, 2018;Leung et al, 2019;Manzotti et al, 2019;Ryals et al, 2018). An attempt to address the reproducibility question was presented by De Abrew et al, in which they generated an independent CMap-style dataset for 34 compounds in four cell lines (De Abrew et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Connectivity Map shows limited reproducibility in drug repositioning

Lim

Pavlidis

2019

Preprint

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The Connectivity Map (CMap) is a popular resource designed for data-driven drug repositioning using a large transcriptomic compendium. However, evaluations of its performance are limited. We used two iterations of CMap (CMap 1 and 2) to assess their comparability and reliability. We queried CMap 2 with CMap 1-derived signatures, expecting CMap 2 would highly prioritize the queried compounds; success rate was 17%. Analysis of previously published prioritizations yielded similar results. Low recall is caused by low differential expression (DE) reproducibility both between CMaps and within each CMap.DE strength was predictive of reproducibility, and is influenced by compound concentration and cell-line responsiveness. Reproducibility of CMap 2 sample expression levels was also lower than expected. We attempted to identify the "better" CMap by comparison with a third dataset, but they were mutually discordant. Our findings have implications for CMap usage and we suggest steps for investigators to limit false positives.

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“…The contribution of cPLA2 specifically to atherosclerosis has been less studied, but there are a few studies suggesting involvement. Patients with advanced-stage cardiovascular disease had increased vascular cPLA2 expression compared to those with early-stage cardiovascular disease [ 113 ]. Treatment with the cPLA2 inhibitor AACOF3 in a cholecalciferol-overload mouse model significantly reduced vascular calcification [ 113 ].…”

Section: Cytosolic Phospholipase A2mentioning

confidence: 99%

“…Patients with advanced-stage cardiovascular disease had increased vascular cPLA2 expression compared to those with early-stage cardiovascular disease [ 113 ]. Treatment with the cPLA2 inhibitor AACOF3 in a cholecalciferol-overload mouse model significantly reduced vascular calcification [ 113 ]. These studies suggest cPLA2 is involved in vascular calcification during advanced atherosclerosis.…”

Section: Cytosolic Phospholipase A2mentioning

confidence: 99%

Interface of Phospholipase Activity, Immune Cell Function, and Atherosclerosis

et al. 2020

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Phospholipases are a family of lipid-altering enzymes that can either reduce or increase bioactive lipid levels. Bioactive lipids elicit signaling responses, activate transcription factors, promote G-coupled-protein activity, and modulate membrane fluidity, which mediates cellular function. Phospholipases and the bioactive lipids they produce are important regulators of immune cell activity, dictating both pro-inflammatory and pro-resolving activity. During atherosclerosis, pro-inflammatory and pro-resolving activities govern atherosclerosis progression and regression, respectively. This review will look at the interface of phospholipase activity, immune cell function, and atherosclerosis.

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Systems biology identifies cytosolic PLA2 as a target in vascular calcification treatment

Cited by 29 publications

References 48 publications

Molecular Changes in Tissue Proteome during Prostate Cancer Development: Proof-of-Principle Investigation

Molecular Changes in Tissue Proteome during Prostate Cancer Development: Proof-of-Principle Investigation

Evaluation of Connectivity Map shows limited reproducibility in drug repositioning

Interface of Phospholipase Activity, Immune Cell Function, and Atherosclerosis

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