Abstract 22: Histone Deacetylase (HDAC) 4 Controls Neointimal Hyperplasia via Stimulating Proliferation and Migration of Vascular Smooth Muscle Cells

Histone deacetylases (HDACs) are transcriptional co-regulators. We have recently demonstrated that a class IIa HDAC, HDAC4 promotes reactive oxygen species (ROS)-dependent vascular smooth muscle inflammation and mediates the development of hypertension in spontaneously hypertensive rats. Pathogenesis of hypertension is in part modulated by vascular structural remodeling via proliferation and migration of vascular smooth muscle cells (SMCs). We thus examined whether HDAC4 controls SMCs proliferation and migration. In rat mesenteric arterial SMCs, small interfering RNA (siRNA) against HDAC4 inhibited platelet-derived growth factor (PDGF)-BB-induced SMCs proliferation as determined by a cell counting (51% inhibition, n=7) or bromodeoxyuridine incorporation assay (95% inhibition, n=6) and migration as determined by Boyden chamber assay (71% inhibition, n=3). Expression and activity of HDAC4 were increased by PDGF-BB (30% increase, n=5 and 170% increase, n=4, respectively). HDAC4 siRNA inhibited phosphorylation of p38 (69% inhibition, n=5) and heat shock protein (HSP) 27 (91% inhibition, n=5) and expression of cyclin D1 (58% inhibition, n=5) as measured by Western blotting. HDAC4 siRNA also inhibited PDGF-BB-induce ROS production as measured fluorometrically using 2’ 7’-dichlorofluorescein diacetate (77% inhibition, n=4) and nicotinamide adenine dinucleotide phosphate oxidase activity as measured by lucigenin assay (61% inhibition, n=4). A Ca 2+ /calmodulin (CaM)-dependent protein kinase (CaMK) II inhibitor, KN93 inhibited PDGF-BB-induced SMCs proliferation (58% inhibition, n=4) and migration (75% inhibition, n=3) as well as phosphorylation of HDAC4 (84% inhibition, n=4). In vivo, a class IIa HDACs inhibitor, MC1568 prevented neointimal hyperplasia in mice carotid ligation model (54% inhibition, n=6). MC1568 also inhibited increased activity of HDAC4 in the neointimal lesions. The present results for the first time demonstrate that HDAC4 controls PDGF-BB-induced SMCs proliferation and migration through activation of p38/HSP27 signals via ROS generation in a CaMKII-dependent manner, which may lead to the neointima hyperplasia in vivo.

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Jujuboside B Inhibits Neointimal Hyperplasia and Prevents Vascular Smooth Muscle Cell Dedifferentiation, Proliferation, and Migration via Activation of AMPK/PPAR-γ Signaling

Frontiers in Pharmacology ◽

10.3389/fphar.2021.672150 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zaixiong Ji ◽

Jiaqi Li ◽

Jianbo Wang

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Neointimal Hyperplasia ◽

Muscle Cells ◽

Cell Dedifferentiation ◽

Ppar Γ ◽

And Migration ◽

Proliferation And Migration

The uncontrolled proliferation and migration of vascular smooth muscle cells is a critical step in the pathological process of restenosis caused by vascular intimal hyperplasia. Jujuboside B (JB) is one of the main biologically active ingredients extracted from the seeds of Zizyphus jujuba (SZJ), which has the properties of anti-platelet aggregation and reducing vascular tension. However, its effects on restenosis after vascular intervention caused by VSMCs proliferation and migration remain still unknown. Herein, we present novel data showing that JB treatment could significantly reduce the neointimal hyperplasia of balloon-damaged blood vessels in Sprague-Dawley (SD) rats. In cultured VSMCs, JB pretreatment significantly reduced cell dedifferentiation, proliferation, and migration induced by platelet-derived growth factor-BB (PDGF-BB). JB attenuated autophagy and reactive oxygen species (ROS) production stimulated by PDGF-BB. Besides, JB promoted the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ). Notably, inhibition of AMPK and PPAR-γ partially reversed the ability of JB to resist the proliferation and migration of VSMCs. Taken as a whole, our findings reveal for the first time the anti-restenosis properties of JB in vivo and in vitro after the endovascular intervention. JB antagonizes PDGF-BB-induced phenotypic switch, proliferation, and migration of vascular smooth muscle cells partly through AMPK/PPAR-γ pathway. These results indicate that JB might be a promising clinical candidate drug against in-stent restenosis, which provides a reference for further research on the prevention and treatment of vascular-related diseases.

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Mangiferin Inhibits PDGF-BB-Induced Proliferation and Migration of Rat Vascular Smooth Muscle Cells and Alleviates Neointimal Formation in Mice through the AMPK/Drp1 Axis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/3119953 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Qi Wu ◽

Yuanyang Chen ◽

Zhiwei Wang ◽

Xin Cai ◽

Yanjia Che ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Neointimal Hyperplasia ◽

Muscle Cells ◽

Neointimal Formation ◽

Artery Ligation ◽

And Migration ◽

Proliferation And Migration

Mangiferin is a naturally occurring xanthone C-glycoside that is widely found in various plants. Previous studies have reported that mangiferin inhibits tumor cell proliferation and migration. Excessive proliferation and migration of vascular smooth muscle cells (SMCs) is associated with neointimal hyperplasia in coronary arteries. However, the role and mechanism of mangiferin action in neointimal hyperplasia is still unknown. In this study, a mouse carotid artery ligation model was established, and primary rat smooth muscle cells were isolated and used for mechanistic assays. We found that mangiferin alleviated neointimal hyperplasia, inhibited proliferation and migration of SMCs, and promoted platelets derive growth factors-BB- (PDGF-BB-) induced contractile phenotype in SMCs. Moreover, mangiferin attenuated neointimal formation by inhibiting mitochondrial fission through the AMPK/Drp1 signaling pathway. These findings suggest that mangiferin has the potential to maintain vascular homeostasis and inhibit neointimal hyperplasia.

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LncRNA SNHG12 promotes proliferation and migration of vascular smooth muscle cells via targeting miR-766-5p/ EIF5A

10.21203/rs.3.rs-27364/v1 ◽

2020 ◽

Author(s):

wen liu ◽

jianhuan che ◽

Yan Gu ◽

ling song ◽

yingying Jiao ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Muscle Cells ◽

Translation Initiation Factor ◽

Cell Counting ◽

Luciferase Reporter ◽

And Migration ◽

Proliferation And Migration

Abstract Background Although lncRNAs have reported to serve as potential biomarkers of atherosclerosis (AS), the role of lncRNA SNHG12 in AS are still unknown. Methods In present study, we investigated the regulatory effects of SNHG12 on human vascular smooth muscle cells (hVSMCs). RT-qPCR were employed to determine the expressions of SNHG12, miR-766-5p and eukaryotic translation initiation factor 5A (EIF5A). Cell viability was estimated via the Cell Counting Kit-8 assay. Wound healing and Transwell invasion assays were used for evaluation of hVSMCs migratory capacity. To further investigate the regulatory mechanisms, binding sites between SNHG12 and miR-766-5p, EIF5A and miR-766-5p were speculated via starBase V2.0, and validated using luciferase reporter gene assay. Results It was identified that SNHG12 was up-regulated in oxidized low-density lipoprotein (ox-LDL)-insulted hVSMCs. Silencing SNHG12 inhibited ox-LDL-induced proliferation and migration of hVSMCs. Moreover, we found that SNHG12 acted as a sponge of miR-766-5p, and miR-766-5p also interacted with EIF5A. EIF5A plasmids promoted the proliferation and migratory capacities of hVSMCs, however, shRNA-SNHG12 counteracted the facilitation of EIF5A plasmids on biological behaviors of hVSMCs. Conclusions These findings of this study demonstrated that SNHG12 facilitated the migration and invasion of hVSMCs via targeting miR-766-5p/EIF5A axis.

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SIRT7 Regulates the Vascular Smooth Muscle Cells Proliferation and Migration via Wnt/β-Catenin Signaling Pathway

BioMed Research International ◽

10.1155/2018/4769596 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 15

Author(s):

Jianghua Zheng ◽

Kai Chen ◽

Haifei Wang ◽

Zhilong Chen ◽

Yong Xi ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Muscle Cells ◽

Cell Counting ◽

Cell Proliferation And Migration ◽

And Migration ◽

Proliferation And Migration

A huge amount of evidence indicates that sirtuin 7 (SIRT7), a key mediator of many cellular activities, plays a crucial role in the pathogenesis of various diseases. However, little is known about the role of SIRT7 in atherosclerosis. This study investigated the potential role of SIRT7 in regulating the proliferation and migration of human vascular smooth muscle cells (HAVSMCs) and its possible molecular mechanism. In this study, human vascular smooth muscle cells (HAVSMCs) were induced by oxidized low-density lipoprotein (ox-LDL) to establish atherosclerosis (AS) cell model. Immunofluorescence staining and Western blot were used to detect the level of α-SMA expression, which was a marker protein in AS. In addition, RT-qPCR and Western blot assay were applied for exploring the mRNA and protein expression levels of SIRT7, Wnt, β-catenin, and cyclin D1 after knockdown or overexpression of SIRT7. And, furthermore, Cell Counting Kit-8 assay, flow cytometry, and wound-healing assay were used to assess HAVSMCs proliferation, cell cycle, and migration. Dickkopf-1 (DKK-1), a secretory glycoprotein that can block Wnt/β-catenin pathway, was used in SIRT7 overexpression HAVSMCs; subsequently cells proliferation and migration were assessed by Cell Counting Kit-8 assay, flow cytometry analysis, and wound-healing assay. We found that knockdown of SIRT7 significantly promoted cell proliferation and migration, decreased the percentages of cells in the G1 and G2 phases, and increased those in the S phase and downregulated the protein expression levels of Wnt, β-catenin, and cyclin D1, while overexpression of SIRT7 had reverse results. After treatment with Wnt/beta-catenin pathway inhibitor DKK-1 in SIRT7 overexpression HAVSMCs, cell proliferation and migration were increased, respectively. In conclusion, SIRT7 inhibited HAVSMCs proliferation and migration via enhancing Wnt/β-catenin activation, which provided a novel therapeutic strategy for antiatherosclerosis.

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Downregulation of Cavin‐1 Expression via Increasing Caveolin‐1 Degradation Prompts the Proliferation and Migration of Vascular Smooth Muscle Cells in Balloon Injury–Induced Neointimal Hyperplasia

Journal of the American Heart Association ◽

10.1161/jaha.117.005754 ◽

2017 ◽

Vol 6 (8) ◽

Cited By ~ 7

Author(s):

Li‐Jun Zhou ◽

Xue‐Ying Chen ◽

Shui‐Ping Liu ◽

Lin‐Lin Zhang ◽

Ya‐Nan Xu ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Neointimal Hyperplasia ◽

Muscle Cells ◽

Balloon Injury ◽

Caveolin 1 ◽

And Migration ◽

Proliferation And Migration

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GW29-e0982 Cantharidin inhibits neointimal hyperplasia by suppressing inflammation and the proliferation and migration of vascular smooth muscle cells

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2018.08.123 ◽

2018 ◽

Vol 72 (16) ◽

pp. C33

Author(s):

Liqiang Qiu ◽

Hao Xia ◽

Hong Jiang ◽

Changwu Xu

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Neointimal Hyperplasia ◽

Muscle Cells ◽

And Migration ◽

Proliferation And Migration

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Histone Deacetylase 4 Controls Neointimal Hyperplasia via Stimulating Proliferation and Migration of Vascular Smooth Muscle Cells

Hypertension ◽

10.1161/hypertensionaha.113.01843 ◽

2014 ◽

Vol 63 (2) ◽

pp. 397-403 ◽

Cited By ~ 50

Author(s):

Tatsuya Usui ◽

Tomoka Morita ◽

Muneyoshi Okada ◽

Hideyuki Yamawaki

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Histone Deacetylase ◽

Vascular Smooth Muscle Cells ◽

Neointimal Hyperplasia ◽

Muscle Cells ◽

Histone Deacetylase 4 ◽

And Migration ◽

Proliferation And Migration

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MiR-506-3p Promotes the Proliferation and Migration of Vascular Smooth Muscle Cells via Targeting KLF4

Pathobiology ◽

10.1159/000513506 ◽

2021 ◽

pp. 1-12

Author(s):

Hang Dong ◽

Guangyu Jiang ◽

Jiayue Zhang ◽

Yuming Kang

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Muscle Cells ◽

Cell Counting ◽

Luciferase Reporter ◽

Qrt Pcr ◽

And Migration ◽

Proliferation And Migration

Background: The dysregulation of proliferation and migration of vascular smooth muscle cells (VSMCs) is one of the major causes of atherosclerosis (AS). Accumulating studies confirm that Kruppel-like factor 4 (KLF4) can regulate the proliferation and differentiation of VSMCs through multiple signaling pathways. However, the mechanism of KLF4 dysregulation remains unknown. Methods: Apolipoprotein E-knockout (ApoE−/−) mice and human VSMCs were used to establish AS animal model and cell model, respectively. qRT-PCR was employed to determine the expressions of miR-506-3p and KLF4. Cell Counting Kit -8, Transwell, TUNEL assays, and flow cytometry were performed to measure the proliferation, migration, and apoptosis of VSMCs. The upstream miRNAs of KLF4 were predicted by microT, miRanda, miRmap, and TargetScan databases. The interaction between KLF4 and miR-506-3p was confirmed using qRT-PCR, Western blot, and luciferase reporter gene assay. Results: KLF4 expression was significantly decreased in the VSMCs of ApoE−/− mice fed with high-fat diet and in human VSMCs treated with oxidized low-density lipoprotein in time-dependent and dose-dependent manners. The transfection of miR-506-3p mimics or KLF4 shRNA promoted the proliferation and migration of VSMCs but inhibited the apoptosis while miR-506-3p inhibitors and pcDNA3.1-KLF4 exerted opposite effects. Additionally, KLF4 was confirmed as a target gene of miR-506-3p and could be negatively regulated by miR-506-3p. Conclusion: MiR-506-3p can promote the proliferation and migration of VSMCs via targeting KLF4, which can probably contribute to the pathogenesis of AS.

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