Omics‐based approaches to understand mechanosensitive endothelial biology and atherosclerosis

Simmons, Rachel; Kumar, Sandeep; Thabet, Salim; Sur, Sandeepa; Jo, Hanjoong

doi:10.1002/wsbm.1344

Cited by 16 publications

(15 citation statements)

References 234 publications

(477 reference statements)

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“…The overexpressed genes found in both datasets in E8's in comparison to E2's were subjected to a Panther (http://www.pantherdb.org/) Gene Ontology (GO) analysis (Mi et al, 2017). As shown in Figure 3B, ECs exposed to chronic d-flow exhibited induction of many well-known biological processes associated with proatherogenic pathways (Simmons et al, 2016). These include vascular development, inflammation, apoptosis, angiogenesis, EndMT, TGF-β pathway and endothelial permeability (Daniel and van Buul, 2013;DePaola et al, 1999;Fan and Karino, 2010;Jenkins et al, 2013;Johnson and Nerem, 2007;Kutikhin et al, 2018;Rocha et al, 2018;Schnittler, 1998;Seebach et al, 2000;Ueno et al, 2000;Yamamoto et al, 2003).…”

Section: D-flow Induces Pro-atherogenic Pathways In Ecsmentioning

confidence: 99%

“…Atherosclerosis is a chronic inflammatory disease and occurs preferentially in arterial regions exposed to disturbed blood flow (d-flow), while those exposed to stable flow (s-flow) are protected (Chiu and Chien, 2011;Kwak et al, 2014;Tarbell et al, 2014). Flow is recognized by mechanosensors in endothelial cells (ECs), which in turn activate signaling pathways leading to regulation of gene expression, endothelial function, and atherogenic pathways (Simmons et al, 2016). D-flow induces crucial pro-atherogenic pathways in ECs including endothelial inflammation and dysfunction, permeability dysfunction, thrombosis, and endothelial-to-mesenchymal transition (EndMT).…”

Section: Introductionmentioning

confidence: 99%

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Endothelial reprogramming by disturbed flow revealed by single-cell RNA and chromatin accessibility study

Andueza

Kumar

Kim

et al. 2020

Preprint

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SUMMARYDisturbed flow (d-flow) induces atherosclerosis by regulating gene expression in endothelial cells (ECs). For further mechanistic understanding, we carried out a single-cell RNA sequencing (scRNAseq) and scATACseq study using endothelial-enriched single-cells from the left- and right carotid artery exposed to d-flow (LCA) and stable-flow (s-flow in RCA) using the mouse partial carotid ligation (PCL) model. We found 8 EC clusters along with immune cells, fibroblasts, and smooth muscle cells. Analyses of marker genes, pathways, and pseudo-time revealed that ECs are highly heterogeneous and plastic. D-flow induced a dramatic transition of ECs from atheroprotective phenotypes to pro-inflammatory, mesenchymal (EndMT), hematopoietic stem cells, endothelial stem/progenitor cells, and an unexpected immune cell-like (EndICLT) phenotypes. While confirming KLF4/KLF2 as s-flow-sensitive transcription factor binding site, we also found those sensitive to d-flow (RELA, AP1, STAT1, and TEAD1). D-flow reprograms ECs from atheroprotective to pro-atherogenic phenotypes including EndMT and potentially EndICLT.

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Section: D-flow Induces Pro-atherogenic Pathways In Ecsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Endothelial reprogramming by disturbed flow revealed by single-cell RNA and chromatin accessibility study

Andueza

Kumar

Kim

et al. 2020

Preprint

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“…under shear stress conditions 11 . The consistent message coming out from such studies is that a healthy blood flow provokes an endothelial transcriptional program characterized by increased expression of anti-inflammatory, anti-adhesive and anti-thrombotic factors 6,12 . Of the many factors identified, the zinc finger transcription factor Krüppel-like factor (KLF2) 13 has emerged as a master regulator of the atheroprotective transcriptional program in the endothelium 14,15 and in various myeloid-derived cell types 16,17 .…”

mentioning

confidence: 93%

“…High-shear stress at the endothelial surface induces KLF2, reducing inflammatory activation and antithrombotic properties [18][19][20] . Crucially, these studies underline the active role of the endothelial cells and leukocytes as key regulators of vascular function to maintain vascular homeostasis 6,21,22 . Modified lipoproteins accumulation in the subendothelial space aggravates the endothelial cell dysfunction and results in the accumulation of macrophages derived from circulating monocytes in the arterial wall [23][24][25] .…”

mentioning

confidence: 99%

The pharmaceutical solvent N-methyl-2-pyrollidone (NMP) attenuates inflammation through Krüppel-like factor 2 activation to reduce atherogenesis

Roche-Molina

Hardwick

Sánchez‐Ramos

et al. 2020

Sci Rep

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N-methyl-2-pyrrolidone (NMP) is a versatile water-miscible polar aprotic solvent. It is used as a drug solubilizer and penetration enhancer in human and animal, yet its bioactivity properties remain elusive. Here, we report that NMP is a bioactive anti-inflammatory compound well tolerated in vivo, that shows efficacy in reducing disease in a mouse model of atherosclerosis. Mechanistically, NMP increases the expression of the transcription factor Kruppel-like factor 2 (KLF2). Monocytes and endothelial cells treated with NMP express increased levels of KLF2, produce less pro-inflammatory cytokines and adhesion molecules. We found that NMP attenuates monocyte adhesion to endothelial cells inflamed with tumor necrosis factor alpha (TNF-α) by reducing expression of adhesion molecules. We further show using KLF2 shRNA that the inhibitory effect of NMP on endothelial inflammation and subsequent monocyte adhesion is KLF2 dependent. Enhancing KLF2 expression and activity improves endothelial function, controls multiple genes critical for inflammation, and prevents atherosclerosis. Our findings demonstrate a consistent effect of NMP upon KLF2 activation and inflammation, biological processes central to atherogenesis. Our data suggest that inclusion of bioactive solvent NMP in pharmaceutical compositions to treat inflammatory disorders might be beneficial and safe, in particular to treat diseases of the vascular system, such as atherosclerosis. Atherosclerosis poses a significant burden to healthcare systems throughout the world. Without access to new, inexpensive treatments, atherosclerosis and its associated cardiovascular complications will likely remain a leading cause of morbidity and mortality worldwide 1. A compelling body of evidence now describes the importance of endothelial dysfunction and inflammation during the development of atherosclerosis 2 , evidence which has driven the pharmaceutical industry to target inflammatory pathways in the quest for novel therapeutic strategies 3-5. The classical view states that the initial step of inflammation during atherosclerosis depends on the activation of the vascular endothelium 6. It is now evident that biomechanical forces exerted upon the endothelial layers by blood flow play a significant role in the resolution of inflammatory insults 7,8. Gene expression studies have demonstrated major differences in the transcriptional profile exerted upon the endothelium by a healthy, laminar blood flow compared to the complex and turbulent flow associated with early sites of atherosclerotic lesions 6,9,10. These studies have been extensively recapitulated in in vitro studies on endothelial cell monolayers

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“…Indeed, since atherosclerosis remains the leading cause of death, epigenomics, transcriptomics, proteomics and metabolomics approaches are increasingly adopted by the scientific community. 80…”

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confidence: 99%

Atherosclerosis: Beyond the lipid storage hypothesis. The role of autoimmunity

Cinoku

Mavragani

Moutsopoulos

2020

Eur J Clin Investigation

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Atherosclerosis has long been considered as a lipid storage disease. Recent data suggest that autoimmune mechanisms seem to be involved in the pathophysiology of atherosclerosis. The presence of activated endothelial vascular cells, neutrophils, macrophages, T and to a lesser extent B cells in atherosclerotic plaques, together with the proinflammatory cytokine burden suggest mobilization of both innate and adaptive immune pathways in atherosclerosis pathobiology. The development of antibodies to oxidized low-density lipoprotein (ox-LDL), the experimental induction of atherosclerosis either via the transfer of T cells or immunization with autoantigens such as β2 glycoprotein Ι (β2-GPI) and heat shock proteins (HSP) further support the autoimmune nature of atherosclerosis. However, classical immunosuppressive and immune-modulatory drugs, successfully used in the therapy of autoimmune rheumatic diseases have shown limited benefits so far in the treatment of atherosclerosis. K E Y W O R D Satherosclerosis, autoimmune disease, autoimmune response, oxidized form of low-density lipoprotein

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Omics‐based approaches to understand mechanosensitive endothelial biology and atherosclerosis

Cited by 16 publications

References 234 publications

Endothelial reprogramming by disturbed flow revealed by single-cell RNA and chromatin accessibility study

Endothelial reprogramming by disturbed flow revealed by single-cell RNA and chromatin accessibility study

The pharmaceutical solvent N-methyl-2-pyrollidone (NMP) attenuates inflammation through Krüppel-like factor 2 activation to reduce atherogenesis

Atherosclerosis: Beyond the lipid storage hypothesis. The role of autoimmunity

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