Vascular Pharmacology

2015

DOI: 10.1016/j.vph.2015.02.002

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Naturally occurring PDGF receptor inhibitors with potential anti-atherosclerotic properties

Chiara Ricci¹,

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Possible Mechanisms For Pdgf To Enhance Vc1

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Cited by 29 publications

(19 citation statements)

References 94 publications

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“…Platelet‐derived growth factor exists as PDGF‐AA or PDGF‐BB homodimer, or PDGF‐AB heterodimer. It has also been found that PDGF‐BB and PDGFRβ are expressed in VSMCs within atherosclerotic lesions, and that inhibition of PDGF‐BB and PDGFRβ reduces atherosclerotic lesion size . Platelet‐derived growth factor can promote VSMCs to switch from the quiescent contractile phenotype (also known as differentiated state) to the ‘synthetic’ phenotype (also known as dedifferentiated state) by inhibiting expression of VSMC‐specific marker genes such as alpha‐smooth muscle actin (α‐SMA) and calponin .…”

Section: Introductionmentioning

confidence: 99%

microRNA let‐7g suppresses PDGF‐induced conversion of vascular smooth muscle cell into the synthetic phenotype

¹

,

²

,

³

et al. 2017

J Cellular Molecular Medi

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Platelet‐derived growth factor (PDGF) can promote vascular smooth muscle cells (VSMCs) to switch from the quiescent contractile phenotype to synthetic phenotype, which contributes to atherosclerosis. We aimed to investigate the role of microRNA let‐7g in phenotypic switching. Bioinformatics prediction was used to find let‐7g target genes in the PDGF/mitogen‐activated protein kinase kinase kinase 1 (MEKK1)/extracellular signal‐regulated kinase (ERK)/Krüppel‐like factor‐4 (KLF4) signalling pathway that affects VSMC phenotypic switching. The luciferase reporter assay and let‐7g transfection were used to confirm let‐7g target genes. Two contractile proteins alpha‐smooth muscle actin (α‐SMA) and calponin were VSMC‐specific genes and were measured as the indicators for VSMC phenotype. Lentivirus carrying the let‐7g gene was injected to apolipoprotein E knockout (apoE−/−) mice to confirm let‐7g's effect on preventing atherosclerosis. Through the PDGF/MEKK1/ERK/KLF4 signalling pathway, PDGF‐BB can inhibit α‐SMA and calponin. The PDGFB and MEKK1 genes were predicted to harbour let‐7g binding sites, which were confirmed by our reporter assays. Transfection of let‐7g to VSMC also reduced PDGFB and MEKK1 levels. Moreover, we showed that let‐7g decreased phosphorylated‐ERK1/2 while had no effect on total ERK1/2. KLF4 can reduce VSMC‐specific gene expression by preventing myocardin–serum response factor (SRF) complex from associating with these gene promoters. The immunoprecipitation assay showed that let‐7g decreased the interaction between KLF4 and SRF. Further experiments demonstrated that let‐7g can increase α‐SMA and calponin levels to maintain VSMC in the contractile status. Injection of lentivirus carrying let‐7g gene increased let‐7g's levels in aorta and significantly decreased atherosclerotic plaques in the apoE−/− mice. We demonstrated that let‐7g reduces the PDGF/MEKK1/ERK/KLF4 signalling to maintain VSMC in the contractile status, which further reduce VSMC atherosclerotic change.

“…Platelet‐derived growth factor exists as PDGF‐AA or PDGF‐BB homodimer, or PDGF‐AB heterodimer. It has also been found that PDGF‐BB and PDGFRβ are expressed in VSMCs within atherosclerotic lesions, and that inhibition of PDGF‐BB and PDGFRβ reduces atherosclerotic lesion size . Platelet‐derived growth factor can promote VSMCs to switch from the quiescent contractile phenotype (also known as differentiated state) to the ‘synthetic’ phenotype (also known as dedifferentiated state) by inhibiting expression of VSMC‐specific marker genes such as alpha‐smooth muscle actin (α‐SMA) and calponin .…”

Section: Introductionmentioning

confidence: 99%

microRNA let‐7g suppresses PDGF‐induced conversion of vascular smooth muscle cell into the synthetic phenotype

¹

,

²

,

³

et al. 2017

J Cellular Molecular Medi

View full text Add to dashboard Cite

Platelet‐derived growth factor (PDGF) can promote vascular smooth muscle cells (VSMCs) to switch from the quiescent contractile phenotype to synthetic phenotype, which contributes to atherosclerosis. We aimed to investigate the role of microRNA let‐7g in phenotypic switching. Bioinformatics prediction was used to find let‐7g target genes in the PDGF/mitogen‐activated protein kinase kinase kinase 1 (MEKK1)/extracellular signal‐regulated kinase (ERK)/Krüppel‐like factor‐4 (KLF4) signalling pathway that affects VSMC phenotypic switching. The luciferase reporter assay and let‐7g transfection were used to confirm let‐7g target genes. Two contractile proteins alpha‐smooth muscle actin (α‐SMA) and calponin were VSMC‐specific genes and were measured as the indicators for VSMC phenotype. Lentivirus carrying the let‐7g gene was injected to apolipoprotein E knockout (apoE−/−) mice to confirm let‐7g's effect on preventing atherosclerosis. Through the PDGF/MEKK1/ERK/KLF4 signalling pathway, PDGF‐BB can inhibit α‐SMA and calponin. The PDGFB and MEKK1 genes were predicted to harbour let‐7g binding sites, which were confirmed by our reporter assays. Transfection of let‐7g to VSMC also reduced PDGFB and MEKK1 levels. Moreover, we showed that let‐7g decreased phosphorylated‐ERK1/2 while had no effect on total ERK1/2. KLF4 can reduce VSMC‐specific gene expression by preventing myocardin–serum response factor (SRF) complex from associating with these gene promoters. The immunoprecipitation assay showed that let‐7g decreased the interaction between KLF4 and SRF. Further experiments demonstrated that let‐7g can increase α‐SMA and calponin levels to maintain VSMC in the contractile status. Injection of lentivirus carrying let‐7g gene increased let‐7g's levels in aorta and significantly decreased atherosclerotic plaques in the apoE−/− mice. We demonstrated that let‐7g reduces the PDGF/MEKK1/ERK/KLF4 signalling to maintain VSMC in the contractile status, which further reduce VSMC atherosclerotic change.

“…PDGF-BB is a potent mitogen released from injuried vessels, which contributes significantly to VSMCs proliferation. Therefore, it is a promising strategy to look for compounds which suppress PDGF-BB-mediated VSMCs proliferation [8]. Zedoarondiol is a sesquiterpenoid.…”

Section: Discussionmentioning

confidence: 99%

Zedoarondiol Inhibits Platelet-Derived Growth Factor-Induced Vascular Smooth Muscle Cells Proliferation via Regulating AMP-Activated Protein Kinase Signaling Pathway

Mao¹,

Tao²,

et al. 2016

Cell Physiol Biochem

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Background/Aims: Vascular smooth muscle cells (VSMCs) proliferation contributes significantly to atherosclerosis and in-stent restenosis. Platelet-derived growth factor-BB (PDGF-BB) plays a vital role in VSMCs proliferation. Zedoarondiol, a sesquiterpene lactone compound, has an anti-inflammatory activity. However, the role of zedoarondiol in PDGF-BB-mediated VSMCs proliferation remains unclear. In this study, we investigated the effects of zedoarondiol on PDGF-BB-induced VSMCs proliferation and explored the possible mechanisms. Methods: The inhibitory effects of zedoarondiol on PDGF-BB-induced VSMCs proliferation were evaluated by direct cell counting and the Cell Counting Kit-8 (CCK-8) assay. DNA synthesis was examined by bromodeoxyuridine (BrdU) incorporation assay. Cell cycle was assessed by propidium iodide staining. Western blotting was performed to determine the expression of cyclin-dependent kinase 2 (CDK2), cyclin E, p53, p21, total and phosphorylated adenosine monophosphate-activated protein kinase (AMPK), acetyl CoA carboxylase (ACC), mammalian target of rapamycin (mTOR), and p70 ribosomal protein S6 kinase (p70S6K). Results: Zedoarondiol suppressed PDGF-BB-induced VSMCs proliferation and DNA synthesis, and induced cell cycle arrest in G0/G1 phase. In addition, zedoarondiol activated AMPK and ACC, inhibited the phosphorylation of mTOR and p70S6K, increased the expression of p53 and p21, and decreased the expression of CDK2 and cyclin E. Compound C (an AMPK inhibitor) abrogated, whereas 5-aminoimidazole-4-carboxamide 1-β-ribofuranoside (AICAR, an AMPK activator) enhanced zedoarondiol-mediated inhibition of VSMCs proliferation and DNA synthesis. Conclusion: Zedoarondiol inhibits PDGF-BB-induced VSMCs proliferation via AMPK-mediated down-regulation of the mTOR/p70S6K pathway and up-regulation of the p53/p21 pathway. These findings suggest that zedoarondiol might be a promising compound against atherosclerosis and in-stent restenosis.

“…Multiple evidence show that PDGF can act as a potent pro‐migratory factor for cells of mesenchymal origin. During the development of atherosclerosis, VSMCs are mediated by PDGF to migrate from normal location in media to the intima layer of the artery, which may ultimately lead to arterial occlusion (Ricci & Ferri, ).…”

Section: Possible Mechanisms For Pdgf To Enhance Vcmentioning

confidence: 99%

Roles of platelet‐derived growth factor in vascular calcification

¹

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²

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³

et al. 2017

Journal Cellular Physiology

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Vascular calcification (VC) is prevalent in aging, and patients with hypertension, chronic kidney disease (CKD), or diabetes. VC is regarded as an active and complex process that involves multiple mechanisms responsible for calcium deposition in vessel wall. In light of the complicated pathogenesis of VC, effective therapy for ameliorating VC is limited. Thus, it is urgent to explore the potential mechanisms and find new targets for the therapy of VC. Platelet-derived growth factor (PDGF), a potent mitogen, and chemoattractant have been found to disturb the vascular homeostasis by inducing inflammation, oxidative stress, and phenotype transition, all of which accelerate the process of VC. The aim of current review is to present a review about the roles of PDGF in affecting VC and to establish a potential target for treating VC.

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