Differential effects of chlorinated and oxidized phospholipids in vascular tissue: implications for neointima formation

Greig, Fiona H.; Hutchison, Lisa C.; Spickett, Corinne M.; Kennedy, Simon

doi:10.1042/cs20140578

Cited by 21 publications

(12 citation statements)

References 50 publications

(64 reference statements)

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“… 26 Therefore, our study may suggest that C2238/ α ANP induces cellular abnormalities through the inhibition of the above-described pleiotropic effects of ApoE. Furthermore, since higher myeloperoxidase levels were reported in Apo −/− mice, 27 we can postulate that C2238/ α ANP may, at least in part, associate to higher myeloperoxidase levels, as previously reported in coronary artery disease patients, 4 through its ability to lower ApoE gene expression.…”

Section: Discussionsupporting

confidence: 77%

C2238/αANP modulates apolipoprotein E through Egr-1/miR199a in vascular smooth muscle cells in vitro

et al. 2015

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Subjects carrying the T2238C ANP gene variant have a higher risk to suffer a stroke or myocardial infarction. The mechanisms through which T2238C/αANP exerts detrimental vascular effects need to be fully clarified. In the present work we aimed at exploring the impact of C2238/αANP (mutant form) on atherosclerosis-related pathways. As a first step, an atherosclerosis gene expression macroarray analysis was performed in vascular smooth muscle cells (VSMCs) exposed to either T2238/αANP (wild type) or C2238/αANP. The major finding was that apolipoprotein E (ApoE) gene expression was significantly downregulated by C2238/αANP and it was upregulated by T2238/αANP. We subsequently found that C2238/αANP induces ApoE downregulation through type C natriuretic peptide receptor (NPR-C)-dependent mechanisms involving the upregulation of miR199a-3p and miR199a-5p and the downregulation of DNAJA4. In fact, NPR-C knockdown rescued ApoE level. Upregulation of miR199a by NPR-C was mediated by a reactive oxygen species-dependent increase of the early growth response protein-1 (Egr-1) transcription factor. In fact, Egr-1 knockdown abolished the impact of C2238/αANP on ApoE and miR199a. Of note, downregulation of ApoE by C2238/αANP was associated with a significant increase in inflammation, apoptosis and necrosis that was completely rescued by the exogenous administration of recombinant ApoE. In conclusion, our study dissected a novel mechanism of vascular damage exerted by C2238/αANP that is mediated by ApoE downregulation. We provide the first demonstration that C2238/αANP downregulates ApoE in VSMCs through NPR-C-dependent activation of Egr-1 and the consequent upregulation of miR199a. Restoring ApoE levels could represent a potential therapeutic strategy to counteract the harmful effects of C2238/αANP.

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Section: Discussionsupporting

confidence: 77%

C2238/αANP modulates apolipoprotein E through Egr-1/miR199a in vascular smooth muscle cells in vitro

et al. 2015

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“…In this model, the left carotid arteries of mice were partially ligated to induce local fluid flow reduction, which was shown to induce endothelial dysfunction and SMC dedifferenation in these partial ligated carotid arteries (PLCAs) 51,52 . In addition, mice were fed HFD to induce more severe vascular injury with neointima development 53 . We then examined the expression of TFEB and molecular markers for TFEB-autophagy signaling pathway by immunohistochemistry.…”

Section: Resultsmentioning

confidence: 99%

Activation of TFEB ameliorates dedifferentiation of arterial smooth muscle cells and neointima formation in mice with high-fat diet

Wang

Chen

et al. 2019

Cell Death Dis

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Autophagy is recently implicated in regulating vascular smooth muscle cell (SMC) homeostasis and in the pathogenesis of vascular remodeling. Transcription factor EB (TFEB) is a master regulator of autophagy signaling pathways. However, the molecular mechanisms and functional roles of TFEB in SMC homeostasis have not been elucidated. Here, we surveyed the ability of TFEB to regulate autophagy pathway in SMCs, and whether pharmacological activation of TFEB favors SMC homeostasis preventing dedifferentiation and pathogenic vascular remodeling. In primary cultured SMCs, TFEB activator trehalose induced nuclear translocation of TFEB and upregulation of TFEB-controlled autophagy genes leading to enhanced autophagy signaling. Moreover, trehalose suppressed serum-induced SMC dedifferentiation to synthetic phenotypes as characterized by inhibited proliferation and migration. These effects of trehalose were mimicked by ectopic upregulation of TFEB and inhibited by TFEB gene silencing. In animal experiments, partial ligation of carotid arteries induced downregulation of TFEB pathway in the media layer of these arteries. Such TFEB suppression was correlated with increased SMC dedifferentiation and aggravated high-fat diet (HFD)-induced neointima formation. Treatment of mice with trehalose reversed this TFEB pathway suppression, and prevented SMC dedifferentiation and HFD-induced neointima formation. In conclusion, our findings have identified TFEB as a novel positive regulator for autophagy pathway and cellular homeostasis in SMCs. Our data suggest that suppression of TFEB may be an initiating mechanism that promotes SMC dedifferentiation leading to accelerated neointima formation in vascular disorders associated with metabolic stress, whereas trehalose reverses these changes. These findings warrant further evaluation of trehalose in the clinical settings.

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“…To further investigate the role of AMPK in the PVAT on vessel inflammation, we used the mouse carotid wire injury model; characterized by endothelial denudation and infiltration of inflammatory cells throughout the vessel wall (Tennant et al, 2008 ; Greig et al, 2015 ). Briefly, mice ( n = 5 WT and n = 4 KO fed on normal chow) were anesthetized and maintained on 1% isoflurane throughout.…”

Section: Methodsmentioning

confidence: 99%

High Fat Diet Attenuates the Anticontractile Activity of Aortic PVAT via a Mechanism Involving AMPK and Reduced Adiponectin Secretion

et al. 2018

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Background and aim: Perivascular adipose tissue (PVAT) positively regulates vascular function through production of factors such as adiponectin but this effect is attenuated in obesity. The enzyme AMP-activated protein kinase (AMPK) is present in PVAT and is implicated in mediating the vascular effects of adiponectin. In this study, we investigated the effect of an obesogenic high fat diet (HFD) on aortic PVAT and whether any changes involved AMPK.Methods: Wild type Sv129 (WT) and AMPKα1 knockout (KO) mice aged 8 weeks were fed normal diet (ND) or HFD (42% kcal fat) for 12 weeks. Adiponectin production by PVAT was assessed by ELISA and AMPK expression studied using immunoblotting. Macrophages in PVAT were identified using immunohistochemistry and markers of M1 and M2 macrophage subtypes evaluated using real time-qPCR. Vascular responses were measured in endothelium-denuded aortic rings with or without attached PVAT. Carotid wire injury was performed and PVAT inflammation studied 7 days later.Key results: Aortic PVAT from KO and WT mice was morphologically indistinct but KO PVAT had more infiltrating macrophages. HFD caused an increased infiltration of macrophages in WT mice with increased expression of the M1 macrophage markers Nos2 and Il1b and the M2 marker Chil3. In WT mice, HFD reduced the anticontractile effect of PVAT as well as reducing adiponectin secretion and AMPK phosphorylation. PVAT from KO mice on ND had significantly reduced adiponectin secretion and no anticontractile effect and feeding HFD did not alter this. Wire injury induced macrophage infiltration of PVAT but did not cause further infiltration in KO mice.Conclusions: High-fat diet causes an inflammatory infiltrate, reduced AMPK phosphorylation and attenuates the anticontractile effect of murine aortic PVAT. Mice lacking AMPKα1 phenocopy many of the changes in wild-type aortic PVAT after HFD, suggesting that AMPK may protect the vessel against deleterious changes in response to HFD.

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Differential effects of chlorinated and oxidized phospholipids in vascular tissue: implications for neointima formation

Cited by 21 publications

References 50 publications

C2238/αANP modulates apolipoprotein E through Egr-1/miR199a in vascular smooth muscle cells in vitro

C2238/αANP modulates apolipoprotein E through Egr-1/miR199a in vascular smooth muscle cells in vitro

Activation of TFEB ameliorates dedifferentiation of arterial smooth muscle cells and neointima formation in mice with high-fat diet

High Fat Diet Attenuates the Anticontractile Activity of Aortic PVAT via a Mechanism Involving AMPK and Reduced Adiponectin Secretion

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