Vimentin deficiency in macrophages induces increased oxidative stress and vascular inflammation but attenuates atherosclerosis in mice

Håversen, Liliana; Sundelin, Jeanna Perman; Mardinoğlu, Adil; Rutberg, Mikael; Ståhlman, Marcus; Wilhelmsson, Ulrika; Hultén, Lillemor Mattsson; Pekny, Milos; Fogelstrand, Per; Bentzon, Jacob F.; Levin, Malin; Borén, Jan

doi:10.1038/s41598-018-34659-2

Cited by 46 publications

(33 citation statements)

References 76 publications

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“…Our data shows that KPV −/− cells accumulate high levels of glutathione, which we hypothesize is due to an elevated response to oxidative stress. This is in line with a previous finding that vimentin-null cells produce higher levels of ROS compared to wildtype cells (53). Additionally, treatment with WFA induces ROS production in epithelial-derived cancer cells, suggesting that disruption of the vimentin intermediate filament network increases ROS generation (54).…”

Section: Discussionsupporting

confidence: 93%

Vimentin is Required for Tumor Progression and Metastasis in a Mouse Model of Non-Small Cell Lung Cancer

Berr¹,

Wiese²,

Santos³

et al. 2020

Preprint

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1Vimentin, a type III intermediate filament, is highly expressed in aggressive epithelial 2 cancers and is associated with increased rates of metastasis. We show that vimentin is causally 3 required for lung cancer metastasis using a genetic mouse model of lung adenocarcinoma (LSL-4 Kras G12D ;Tp53 fl/fl , termed KPV +/+ ) crossed with vimentin-null mice (thereby creating KPV −/− mice). 5Both KPV +/+ and KPV −/− mice developed lung tumors, yet KPV −/− mice had delayed tumorigenesis 6 and prolonged survival. KPV +/+ cells implanted in the flank metastasized to the lung while KPV −/− 7 cells did not, providing additional evidence that vimentin is required for metastasis. Differential 8 expression analysis of RNA-seq data demonstrated that KPV −/− cells had suppressed expression 9 of genes that drive epithelial-to-mesenchymal transition, migration, and invasion, processes that 10 are critical to the metastatic cascade. Integrative metabolomic and transcriptomic analysis 11 revealed altered glutaminolysis, with KPV −/− cells accumulating glutathione, leading to impaired 12 cell motility in response to oxidative stress. Together, these results show that loss of vimentin 13 impairs epithelial-to-mesenchymal transition and regulation of the oxidative stress response, 14 resulting in decreased metastasis in murine lung adenocarcinoma. 15 16 17 18Non-small-cell lung cancers (NSCLCs) represent 80% of all lung cancers and are often 20 diagnosed at more advanced stages of the disease resulting in high rates of mortality (1). 21Adenocarcinoma is the most common subtype of NSCLC and is characterized by activating 22 mutations in the Kras proto-oncogene in up to 30% of diagnoses and by inactivating mutations in 23 the tumor suppressor gene Tp53 in up to 60% of diagnoses (2)(3)(4)(5). Despite the prevalence of lung 24 adenocarcinoma, the metastatic mechanisms that drive lung cancer progression are incompletely 25 understood. 26The type III intermediate filament vimentin is associated with increased metastatic spread 27 and lower rates of survival in patients with NSCLC (6-8). Vimentin is a canonical marker of 28 epithelial-to-mesenchymal transition (EMT), an initiating event of the metastatic cascade (9). EMT 29 is the process by which epithelial cells remodel cell-cell and cell-extracellular-matrix (ECM) 30 contacts, lose their apical-basal polarity, and adopt the spindle-shaped morphology associated 31 with a mesenchymal cell phenotype (10). During EMT, cells undergo a downregulation of 32 epithelial cell associated genes, including E-cadherin and cytokeratins, and an upregulation of 33 mesenchymal cell associated genes, including N-cadherin and vimentin. In addition to acting as 34 a marker of EMT, vimentin is functionally involved in EMT. Structurally, vimentin intermediate 35 filaments control cell shape, and thus facilitate the transition toward a mesenchymal phenotype 36(11). Twist1, a transcription factor critical to EMT, upregulates vimentin expression (12). Vimentin 37 also serves as a scaffold for Slug, another transc...

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Section: Discussionsupporting

confidence: 93%

Vimentin is Required for Tumor Progression and Metastasis in a Mouse Model of Non-Small Cell Lung Cancer

Berr¹,

Wiese²,

Santos³

et al. 2020

Preprint

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“…Due to the numerous roles of vimentin, the effect of vimentin inhibition in non-malignant cells should be considered. To this end, consequences of its inhibition should be studied in animal models and effects on processes entailing cell migration (such as wound healing [73,133] or immune response [87,134]) should be carefully examined. However, since mice lacking vimentin develop and reproduce without any major problem [135], we can anticipate that beneficial vimentin inhibition in malignant cells outweighs any potential adverse effects.…”

Section: Discussionmentioning

confidence: 99%

Vimentin Intermediate Filaments as Potential Target for Cancer Treatment

Strouhalova

Přechová

Gandalovičová

et al. 2020

Cancers

189

143

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Intermediate filaments constitute the third component of the cellular skeleton. Unlike actin and microtubule cytoskeletons, the intermediate filaments are composed of a wide variety of structurally related proteins showing distinct expression patterns in tissues and cell types. Changes in the expression patterns of intermediate filaments are often associated with cancer progression; in particular with phenotypes leading to increased cellular migration and invasion. In this review we will describe the role of vimentin intermediate filaments in cancer cell migration, cell adhesion structures, and metastasis formation. The potential for targeting vimentin in cancer treatment and the development of drugs targeting vimentin will be reviewed.

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“…In particular, in animal models, it has been described that vimentin deficiency induces oxidative stress and vascular inflammation, while in the uremic setting the decreased vimentin is associated with decreased Klotho expression, configuring a novel specific feature of uremic-related vascular alterations 40 , 41 ) . Interestingly, we made a similar observation, finding that Klotho expression also markedly downregulated in the vascular wall of ESRD patients, when compared to non-uremic donors.…”

Section: Discussionmentioning

confidence: 99%

Myostatin in the Arterial Wall of Patients with End-Stage Renal Disease

Esposito

Verzola

Porta

et al. 2020

JAT

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The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Original Article Aim: Myostatin (Mstn) has been described as a trigger for the progression of atherosclerosis. In this study, we evaluated the role of Mstn in arterial remodeling in patients with end-stage renal disease (ESRD). Methods: Vascular specimens were collected from 16 ESRD patients (56.4 7.9 years) undergoing renal transplant (recipients) and 15 deceased kidney non-uremic donors (55.4 12.1 years). We studied gene and protein expression of Mstn, ubiquitin ligases, Atrogin-1, and muscle ring finger protein-1 (MuRF-1), inflammatory marker CCL2, cytoskeleton components, and Klotho by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Moreover, we assessed vascular calcification and collagen deposition. Finally, we studied the effects of recombinant Mstn on rat vascular smooth muscle cells (VSMCs, A7r5) and evaluated the effects of uremic serum (US) on primary human VSMCs. Results: Myostatin mRNA was upregulated in the arterial vascular wall of recipients compared with donors (~15folds, p 0.05). This response was accompanied by the upregulation of gene expression of Atrogin-1 and MuRF-1 (2.5-and 10-fold) and CCL2 (3-fold). Conversely, we found downregulation of protein expression of Smoothelin,-smooth muscle actin (-SMA), vimentin, and Klotho (-85%,-50%,-70%, and-80%, respectively; p 0.05) and gene expression of vimentin and Klotho. Exposition of A7r5 to Mstn induced a time-dependent SMAD 2/SMAD 3 phosphorylation and expression of collagen-1 and transforming growth factor (TGF) mRNA, while US induced overexpression of Mstn and Atrogin-1 and downregulation of Smoothelin and Klotho. Conclusions: Our data suggest that uremia might induce vascular Mstn gene expression together with a complex pathway of molecular and structural changes in the vascular wall. Myostatin, in turn, can translate the metabolic alterations of uremia into profibrotic and stiffness inducing signals. ing 2, 3) , endothelial dysfunction, arterial stiffness, and vascular calci fication 4, 5). The development of vascular disease involves the response to a number of insults and a complex interplay between cells resident in the vascular wall, including vascular smooth muscle cells (VSMCs), endothelial cells, and infiltrating cells of the innate and adaptive immune system 6). In particular, in atherosclerosis, VSMCs undergo a shift from a contractile to a synthetic phenotype, accompanied by Copyright©2020 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

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Vimentin deficiency in macrophages induces increased oxidative stress and vascular inflammation but attenuates atherosclerosis in mice

Cited by 46 publications

References 76 publications

Vimentin is Required for Tumor Progression and Metastasis in a Mouse Model of Non-Small Cell Lung Cancer

Vimentin is Required for Tumor Progression and Metastasis in a Mouse Model of Non-Small Cell Lung Cancer

Vimentin Intermediate Filaments as Potential Target for Cancer Treatment

Myostatin in the Arterial Wall of Patients with End-Stage Renal Disease

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