Targeting the phenotypic switch of vascular smooth muscle cells to tackle atherosclerosis

Kansakar, Urna; Jankauskas, Stanislovas S.; Gambardella, Jessica; Santulli, Gaetano

doi:10.1016/j.atherosclerosis.2021.03.034

Cited by 26 publications

(18 citation statements)

References 49 publications

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“…VSMC phenotypic switching is one of the major pathological phenomena underlying many VSMC-involving vascular diseases, atherosclerosis and postangioplasty restenosis (Kansakar et al, 2021), and it has several causes such as mechanical forces, growth factors and cytokines, transcriptional regulation and epigenetics. It was reported that several mediators regulate VSMC phenotypic switching, such as Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) ( Wang et al, 2018), peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) (Zhang et al, 2017), and vascular peroxidase 1 (VPO1) (Peng et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Cytokine‐induced apoptosis inhibitor 1 (CIAPIN1) accelerates vascular remodelling via p53 and JAK2‐STAT3 regulation in vascular smooth muscle cells

Han

Heo

Myung

2021

British J Pharmacology

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Background and purpose: Abnormal vascular smooth muscle cell (VSMC) proliferation and migration lead to neointima formation, which eventually results in cardiovascular hyperplastic diseases. The molecular mechanisms underlying these cellular processes have not been fully understood. Cytokine-induced apoptosis inhibitor 1 (CIAPIN1) has been identified as an anti-apoptotic molecule, but little is known about its target genes and related pathways in VSMC dysfunction or its clinical implication in neointima formation following vascular injury.Experimental approach: Determination, using loss/gain-of-function approaches by gene delivery, of whether CIAPIN1 modulates VSMC proliferation, migration and neointima formation and the underlying mechanisms was carried out. Balloon injury or ligation and local delivery of lentivirus were performed on rat or mouse carotid arteries. Rat aortic smooth muscle cells, the primary cell, was used as the model to evaluate the effect of CIAPIN1 on proliferation and migration.Key results: CIAPIN1 was overexpressed in the neointimal region of rat arteries.CIAPIN1 deficiency markedly inhibited injury-induced or ligation-induced intimal hyperplasia and suppressed PDGF-BB-induced VSMC proliferation, migration and cell cycle progression, while overexpression promoted proliferation, migration and neointima formation. CIAPIN1 negatively regulated Tp53 transcription, which promoted cell cycle progression and migration via cyclin E1-CDK2/pRb/PCNA and the MMP2 pathway. CIAPIN1 also increased JAK2 expression, enhancing JAK2 and STAT3 phosphorylation by vascular injury, which forced phenotypic switching from contractile to synthetic state in injured arteries.Conclusions and implications: These findings provide new insights into the mechanism by which CIAPIN1 regulates vascular remodelling and suggest a novel therapeutic target for treating vascular proliferative diseases.

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Section: Discussionmentioning

confidence: 99%

Cytokine‐induced apoptosis inhibitor 1 (CIAPIN1) accelerates vascular remodelling via p53 and JAK2‐STAT3 regulation in vascular smooth muscle cells

Han

Heo

Myung

2021

British J Pharmacology

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“…For the treatment of AS, there is no specific drug at present and it mainly focuses on the comprehensive management of patients, lowering blood glucose and blood lipids, etc. In the future, targeted therapies targeting different cell types in vivo, such as monocyte-macrophage lines37 and regulating VSMC phenotypic switching,38 could be considered. Another study found that the Hsp90 inhibitor 17-DMAG attenuates oxidative stress in experimental AS 39.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Hsp90α, which participates in vascular inflammation, is a novel serum predictor of atherosclerosis in type 2 diabetes

Ding

Meng

Dong

et al. 2022

BMJ Open Diab Res Care

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IntroductionAtherosclerosis is the main pathological change in diabetic angiopathy, and vascular inflammation plays an important role in early atherosclerosis. Extracellular heat shock protein 90 (eHsp90) is secreted into the serum and is involved in various physiological and pathophysiological processes. However, the specific mechanism of eHsp90 in early atherosclerosis remains unclear. This study explored the relationship between Hsp90 and diabetic lower extremity arterial disease and investigated the expression of eHsp90 in vascular endothelial cells under environmental stimulation and the function and mechanism of eHsp90α involved in diabetic atherosclerosis.Research design and methodsOne hundred and three selected patients were divided into three groups: the diabetes mellitus group (n=27), the diabetic lower extremity arterial disease group (n=46), and the diabetic critical limb ischemia group (n=30). The relationships among serum Hsp90, oxidative stress indexes, and patient outcomes and the correlations among the indexes were analyzed. H&E staining and immunohistochemistry were used to observe the vasculature of amputated feet from patients with diabetic foot. An oxidative stress endothelial injury model was established under high glucose in vitro to explore the role of eHsp90 release in atherosclerosis progression.ResultsThe level of serum Hsp90 was upregulated with aggravation of diabetic vascular disease. Hsp90α was correlated with malondialdehyde to some extent and was an independent risk factor in the progression of diabetic vascular disease, with predictive ability. The expression area of Hsp90α was consistent with the area of inflammatory infiltration in the vessel lumen. Vascular endothelial cells were found to increase eHsp90α secretion under stress. Then inhibition of eHsp90α can reduce the degree of cellular inflammation and damage. Endothelial cell-conditioned medium and recombinant human Hsp90α increased monocyte migration via the low-denisity lipoprotein receptor-related protein 1 (LRP1) receptor to promote disease progression.ConclusionseHsp90α plays a critical role in the early inflammatory injury stage of atherosclerosis.Trial registration numberNCT04787770.

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“…Alterations in diverse environmental factors modulate the transcriptional regulation of VSMC-specific genes in AS and arterial remodeling (Jaminon et al, 2019;Shi et al, 2019). Main transcription factors involved in VSMC phenotype switch thereby are Krüppel-like factor 4 (KLF4) by activating the pluripotency network of VSMC (Shankman et al, 2015;Jaminon et al, 2019), the master regulator myocardin (MYOCD)-serum response factor (SRF) regulated by, among others, Olfactomedin 2 and Transcription factor 21 (TCF21) (Shi et al, 2019;Nagao et al, 2020), and octamer binding transcription factor (Oct4) promoting plaque stabilization (Alencar et al, 2020;Kansakar et al, 2021).…”

Section: Factors Regulating Vsmc Phenotype Switching and Arterial Remodelingmentioning

confidence: 99%

Epigenetic Regulation of Vascular Smooth Muscle Cell Phenotype Switching in Atherosclerotic Artery Remodeling: A Mini-Review

et al. 2021

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Atherosclerosis is a chronic inflammatory disease characterized by extensive remodeling of medium and large-sized arteries. Inward remodeling (=lumen shrinkage) of the vascular walls is the underlying cause for ischemia in target organs. Therefore, inward remodeling can be considered the predominant feature of atherosclerotic pathology. Outward remodeling (=lumen enlargement) is a physiological response compensating for lumen shrinkage caused by neointimal hyperplasia, but as a pathological response to changes in blood flow, outward remodeling leads to substantial arterial wall thinning. Thinned vascular walls are prone to rupture, and subsequent thrombus formation accounts for the majority of acute cardiovascular events. Pathological remodeling is driven by inflammatory cells which induce vascular smooth muscle cells to switch from quiescent to a proliferative and migratory phenotype. After decades of intensive research, the molecular mechanisms of arterial remodeling are starting to unfold. In this mini-review, we summarize the current knowledge of the epigenetic and transcriptional regulation of vascular smooth muscle cell phenotype switching from the contractile to the synthetic phenotype involved in arterial remodeling and discuss potential therapeutic options.

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Targeting the phenotypic switch of vascular smooth muscle cells to tackle atherosclerosis

Cited by 26 publications

References 49 publications

Cytokine‐induced apoptosis inhibitor 1 (CIAPIN1) accelerates vascular remodelling via p53 and JAK2‐STAT3 regulation in vascular smooth muscle cells

Cytokine‐induced apoptosis inhibitor 1 (CIAPIN1) accelerates vascular remodelling via p53 and JAK2‐STAT3 regulation in vascular smooth muscle cells

Extracellular Hsp90α, which participates in vascular inflammation, is a novel serum predictor of atherosclerosis in type 2 diabetes

Epigenetic Regulation of Vascular Smooth Muscle Cell Phenotype Switching in Atherosclerotic Artery Remodeling: A Mini-Review

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