Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of CDK9 attenuates atherosclerosis by inhibiting inflammation and phenotypic switching of vascular smooth muscle cells.

ABSTRACT:

Background

Recent studies have demonstrated a key role of vascular smooth muscle cell (VSMC) dysfunction in atherosclerosis. Cyclin-dependent kinases 9 (CDK9), a potential biomarker of atherosclerosis, was significantly increased in coronary artery disease patient serum and played an important role in inflammatory diseases. This study was to explore the pharmacological role of CDK9 inhibition in attenuating atherosclerosis.

Methods

A small-molecule CDK9 inhibitor, LDC000067, was utilized to treat the high fat diet (HFD)-fed ApoE^-/- mice and human VSMCs.

Results

The results showed that inflammation and phenotypic switching of VSMCs were observed in HFD-induced atherosclerosis in ApoE^-/- mice, which were accompanied with increased CDK9 in the serum and atherosclerotic lesions where it colocalized with VSMCs. LDC000067 treatment significantly suppressed HFD-induced inflammation, proliferation and phenotypic switching of VSMCs, resulting in reduced atherosclerosis in the ApoE^-/- mice, while had no effect on plasma lipids. Further in vitro studies confirmed that LDC000067 and siRNA-mediated CDK9 knockdown reversed ox-LDL-induced inflammation and phenotypic switching of VSMCs from a contractile phenotype to a synthetic phenotype via inhibiting NF-κB signaling pathway in human VSMCs.

Conclusion

These results indicate that inhibition of CDK9 may be a novel therapeutic target for the prevention of atherosclerosis.

SUBMITTER: Huang S

PROVIDER: S-EPMC8221363 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Tanshinone II A attenuates vascular remodeling through klf4 mediated smooth muscle cell phenotypic switching.

Project description:The aim of this study is to investigate the therapeutic role of Tanshinone II A, a key integrant from salvia miltiorrhiza, against pathological vascular remodeling. Completed ligation of mouse left common carotid arteries animal model and rat smooth muscle cells used to investigate the role of Tanshinone II A in regulating pathological vascular remodeling through hematoxylin and eosin staining, immunohistochemistry staining, immunofluorescence staining, adenovirus infection, real time PCR and western blotting. Our data demonstrated that Tanshinone II A treatment suppresses vascular injury-induced neointima formation. In vitro studies on rat smooth muscle cell indicated that Tanshinone II A treatment attenuates PDGF-BB induced cell growth, and promotes smooth muscle cell differentiated marker genes expression that induced by rapamycin treatment. Tanshinone II A treatment significant inhibits rat smooth muscle cell proliferation and migration. Tanshinone II A promotes KLF4 expression during smooth muscle phenotypic switching. Overexpression of KLF4 exacerbates Tanshinone II A mediated smooth muscle cell growth inhibition. Tanshinone II A plays a pivotal role in regulating pathological vascular remodeling through KLF4 mediated smooth muscle cell phenotypic switching. This study demonstrated that Tanshinone II A is a potential therapeutic agent for vascular diseases.

| S-EPMC7431534 | biostudies-literature

Apatinib attenuates phenotypic switching of arterial smooth muscle cells in vascular remodelling by targeting the PDGF Receptor-β.

Project description:Apatinib (YN968D1) is a small-molecule tyrosine kinase inhibitor（TKI）which can inhibit the activity of vascular endothelial growth factor receptor-2 (VEGFR-2). It has been reported that apatinib has anti-tumour effect of inhibiting proliferation and inducing apoptosis of a variety of solid tumour cells, whereas its effect on vascular smooth muscle cells (VSMC) remains unclear. This study investigated the effect of apatinib on phenotypic switching of arterial smooth muscle cells in vascular remodelling. Compared to the vehicle groups, mice that were performed carotid artery ligation injury and treated with apatinib produced a reduction in abnormal neointimal area. For in vitro experiment, apatinib administration inhibited VSMC proliferation, migration and reversed VSMC dedifferentiation with the stimulation of platelet-derived growth factor type BB (PDGF-BB).In terms of mechanism, with the preincubation of apatinib, the activations of PDGF receptor-β (PDGFR-β) and phosphoinositide-specific phospholipase C-γ1 (PLC-γ1) induced by PDGF-BB were inhibited in VSMCs. With the preincubation of apatinib, the phosphorylation of PDGFR-β, extracellular signal-related kinases (ERK1/2) and Jun amino-terminal kinases (JNK) induced by PDGF-BB were also inhibited in rat vascular smooth muscle cell line A7r5. Herein, we found that apatinib attenuates phenotypic switching of arterial smooth muscle cells induced by PDGF-BB in vitro and vascular remodelling in vivo. Therefore, apatinib is a potential candidate to treat vascular proliferative diseases.

| S-EPMC7520274 | biostudies-literature

NLRP3 Inflammasome Activation Controls Vascular Smooth Muscle Cells Phenotypic Switch in Atherosclerosis.

Project description:(1) Background: Monocytes and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome orchestrate lipid-driven amplification of vascular inflammation promoting the disruption of the fibrous cap. The components of the NLRP3 inflammasome are expressed in macrophages and foam cells within human carotid atherosclerotic plaques and VSMCs in hypertension. Whether monocytes and NLRP3 inflammasome activation are direct triggers of VSMC phenotypic switch and plaque disruption need to be investigated. (2) Methods: The direct effect of oxLDL-activated monocytes in VSMCs co-cultured system was demonstrated via flow cytometry, qPCR, ELISA, caspase 1, and pyroptosis assay. Aortic roots of VSMCs lineage tracing mice fed normal or high cholesterol diet and human atherosclerotic plaques were used for immunofluorescence quantification of NLRP3 inflammasome activation/VSMCs phenotypic switch. (3) Results: OxLDL-activated monocytes reduced α-SMA, SM22α, Oct-4, and upregulation of KLF-4 and macrophage markers MAC2, F4/80 and CD68 expression as well as caspase 1 activation, IL-1β secretion, and pyroptosis in VSMCs. Increased caspase 1 and IL-1β in phenotypically modified VSMCs was detected in the aortic roots of VSMCs lineage tracing mice fed high cholesterol diet and in human atherosclerotic plaques from carotid artery disease patients who experienced a stroke. (4) Conclusions: Taken together, these results provide evidence that monocyte promote VSMC phenotypic switch through VSMC NLRP3 inflammasome activation with a likely detrimental role in atherosclerotic plaque stability in human atherosclerosis.

| S-EPMC8745068 | biostudies-literature

Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models.

Project description:Transforming growth factor beta-1 (TGFβ1) is a major driver of vascular smooth muscle cell (VSMC) phenotypic switching, an important pathobiology in arterial disease. We performed RNA-sequencing of TGFβ1-stimulated human aortic or arterial VSMCs which revealed large and consistent upregulation of Interleukin 11 (IL11). IL11 has an unknown function in VSMCs, which highly express the IL11 receptor alpha, suggestive of an autocrine loop. In vitro, IL11 activated ERK signaling, but inhibited STAT3 activity, and caused VSMC phenotypic switching to a similar extent as TGFβ1 or angiotensin II (ANGII) stimulation. Genetic or therapeutic inhibition of IL11 signaling reduced TGFβ1- or ANGII-induced VSMC phenotypic switching, placing IL11 activity downstream of these factors. Aortas of mice with Myh11-driven IL11 expression were remodeled and had reduced contractile but increased matrix and inflammatory genes expression. In two models of arterial pressure loading, IL11 was upregulated in the aorta and neutralizing IL11 antibodies reduced remodeling along with matrix and pro-inflammatory gene expression. These data show that IL11 plays an important role in VSMC phenotype switching, vascular inflammation and aortic pathobiology.

| S-EPMC7576123 | biostudies-literature

The GEF Cytohesin-2/ARNO Mediates Resistin induced Phenotypic Switching in Vascular Smooth Muscle Cells.

Project description:The pro-inflammatory adipokine resistin induces a phenotypic switch of vascular smooth muscle cells (VSMC), a process decisive for atherosclerosis, including morphological changes, increased synthetic activity, proliferation and migration. The guanine-exchange factor ARNO (Cytohesin-2) has been shown to be important for morphological changes and migration of other cell types. In this study we dissected the role of ARNO in resistin induced VSMC phenotypic switching and signalling. Firstly, treatment with the cytohesin inhibitor Secin H3 prevented the resistin mediated induction of morphological changes in VSMC. Secondly, Secin H3 treatment as well as expression of an inactive ARNO (EK) reduced resistin induced VSMC synthetic activity, as assessed by matrix metalloproteinase 2 (MMP-2) expression, as well as the migration into a wound in vitro compared to ARNO WT expression. Thirdly, we found ARNO to influence MMP-2 expression and migration via activation of p38 MAPK and the JNK/AP-1 pathway. Interestingly, these processes were shown to be dependent on the binding of PIP3, as mutation of the ARNO PH-domain inhibited VSMC migration, MMP-2 expression as well as p38 MAPK and JNK signalling. Thus, we demonstrate that ARNO is an important link in resistin dependent cell signalling leading to morphological changes, MMP-2 production and migration of VSMC.

| S-EPMC7048779 | biostudies-literature

Network Preservation Analysis Reveals Dysregulated Metabolic Pathways in Human Vascular Smooth Muscle Cell Phenotypic Switching.

Project description:BackgroundVascular smooth muscle cells are key players involved in atherosclerosis, the underlying cause of coronary artery disease. They can play either beneficial or detrimental roles in lesion pathogenesis, depending on the nature of their phenotypic changes. An in-depth characterization of their gene regulatory networks can help better understand how their dysfunction may impact disease progression.MethodsWe conducted a gene expression network preservation analysis in aortic smooth muscle cells isolated from 151 multiethnic heart transplant donors cultured under quiescent or proliferative conditions.ResultsWe identified 86 groups of coexpressed genes (modules) across the 2 conditions and focused on the 18 modules that are least preserved between the phenotypic conditions. Three of these modules were significantly enriched for genes belonging to proliferation, migration, cell adhesion, and cell differentiation pathways, characteristic of phenotypically modulated proliferative vascular smooth muscle cells. The majority of the modules, however, were enriched for metabolic pathways consisting of both nitrogen-related and glycolysis-related processes. Therefore, we explored correlations between nitrogen metabolism-related genes and coronary artery disease-associated genes and found significant correlations, suggesting the involvement of the nitrogen metabolism pathway in coronary artery disease pathogenesis. We also created gene regulatory networks enriched for genes in glycolysis and predicted key regulatory genes driving glycolysis dysregulation.ConclusionsOur work suggests that dysregulation of vascular smooth muscle cell metabolism participates in phenotypic transitioning, which may contribute to disease progression, and suggests that AMT (aminomethyltransferase) and MPI (mannose phosphate isomerase) may play an important role in regulating nitrogen and glycolysis-related metabolism in smooth muscle cells.

| S-EPMC10434832 | biostudies-literature

KLF4-PFKFB3-driven glycolysis is essential for phenotypic switching of vascular smooth muscle cells

Project description:Vascular smooth muscle cells (VSMCs) within atherosclerotic lesions undergo a phenotypic switching in a KLF4-dependent manner. Glycolysis plays important roles in transdifferentiation of somatic cells, however, it is unclear whether and how KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions. Here, we show that KLF4 upregulation accompanies VSMCs phenotypic switching in atherosclerotic lesions. KLF4 enhances the metabolic switch to glycolysis through increasing PFKFB3 expression. Inhibiting glycolysis suppresses KLF4-induced VSMCs phenotypic switching, demonstrating that glycolytic shift is required for VSMCs phenotypic switching. Mechanistically, KLF4 upregulates expression of circCTDP1 and eEF1A2, both of which cooperatively promote PFKFB3 expression. TMAO induces glycolytic shift and VSMCs phenotypic switching by upregulating KLF4. Our study indicates that KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions, suggesting that a previously unrecognized KLF4-eEF1A2/circCTDP1-PFKFB3 axis plays crucial roles in VSMCs phenotypic switching.

2022-11-09 | PXD038057 |

miR-145 attenuates phenotypic transformation of aortic vascular smooth muscle cells to prevent aortic dissection.

Project description:BackgroundmiR-145 is closely related to vascular smooth muscle cells (VSMC) phenotype transformation; however, the regulatory mechanisms through which miR-145 regulates the VSMC phenotype transformation under mechanical stretching are unclear. In this study, we evaluated the roles of miR-145 in VSMCs subjected to mechanical stretching in aortic dissection (AD).MethodsThe expression of miR-145 in the aortic vessel wall of model animals and patients with AD was analyzed by quantitative polymerase chain reaction. miR-145-related protein-protein interaction networks and Wikipathways were used to analyze VSMC phenotypic transformation pathways regulated by miR-145. We used gain- and loss-of-function studies to evaluate the effects of miR-145 on VSMC differentiation under mechanical stretch induction and assessed whether Krüppel-like factor 4 (KLF4) was regulated by miR-145 in the aorta under mechanical stretch conditions.ResultsmiR-145 was abundantly expressed in the walls of the normal human aorta, but was significantly downregulated in animal models and the walls of patients with dissection. We found that contractile phenotype-related proteins were downregulated in VSMCs subjected to mechanical stretching, whereas the expression of secreted phenotype-related proteins increased. miR-145 overexpression also downregulated contractile phenotype-related proteins in VSMCs and suppressed upregulation of phenotype-related proteins. Finally, under mechanical stretching, KLF4 expression was significantly increased in VSMCs, and overexpression of miR-145 blocked this effect.ConclusionOur results confirmed that mechanical stretch-induced phenotypic transformation of VSMCs to promote AD via upregulation of KLF4; this mechanism was regulated by miR-145, which directly modulated KLF4 expression and VSMC differentiation.

| S-EPMC8649326 | biostudies-literature

TWIST1 induces phenotypic switching of vascular smooth muscle cells by downregulating p68 and microRNA-143/145.

Project description:TWIST1 is an important basic helix-loop-helix protein linked to multiple physiological and pathological processes. Although TWIST1 is believed to be involved in vascular pathogenesis, its effects on homeostasis of smooth muscle cells (SMCs) remain poorly understood. Here, we show that TWIST1 protein levels were significantly elevated during SMC phenotypic switching in vivo and in vitro. TWIST1 overexpression promoted phenotypic switching of SMCs, while siRNA targeting of TWIST1 prevented cell transition. Mechanistically, TWIST1 decreased the level of microRNA-143/145, which governs smooth muscle marker gene transcription. In addition, TWIST1 repressed p68 mRNA and protein expression, a crucial modulator of SMC behavior and microRNA biogenesis. Our co-immunoprecipitation assay demonstrated a previously unrecognized molecular interaction between TWIST1 and p68 protein. Finally, we found that TWIST1 triggered SMC phenotypic switching and suppressed microRNA-143/145 expression by promoting the proteasomal degradation of p68. These data suggest a novel role of TWIST1 in the regulation of SMC homeostasis by modulating p68/microRNA-143/145 axis.

| S-EPMC7931233 | biostudies-literature

GPR30 Promotes the Phenotypic Switching of Vascular Smooth Muscle Cells via Activating the AKT and ERK Pathways.

Project description:Background:Lower ?extremity varicose veins (LEVVs) are a common venous disorder of venous dilation and tortuosity. The functional integrity of vascular smooth muscle cells (VSMCs), the majority of the cells in venous tissues, and their phenotypic differences play important roles in the occurrence and development of LEVV. However, the underlying mechanism remains unclear. Methods:The expression of estrogen receptors ER? and ER? and G-protein-coupled receptor 30 (GPR30) in LEVV tissues and the role of GPR30 in VSMC phenotypic switching were examined by Western blotting and quantitative real-time PCR. Finally, the related mechanisms underlying LEVVs were explored by Western blotting. Results:The serum estradiol content was increased in LEVV patients compared with normal control patients, but the mRNA levels of ER? and ER? were not significantly different. GPR30 was overexpressed in LEVVs, and high expression of GPR30 promoted the maintenance of a synthetic phenotype in which OPN, MMP-1 and MMP-9 were highly expressed and ?-SMA was poorly expressed in VSMCs. Finally, the mechanism by which GPR30 promotes the phenotypic switching of VSMCs is dependent on the ERK1/2 and AKT pathways. Conclusion:GPR30 may contribute to the pathogenesis of LEVVs by promoting the maintenance of a synthetic phenotype in VSMCs by activating the ERK1/2 and AKT pathways, and GPR30 might be a novel therapeutic target for clinical LEVV treatment.

| S-EPMC7212987 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data