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Curcumin inhibits the proliferation and migration of vascular smooth muscle cells by targeting the chemerin / CMKLR1 / LCN2 axis.

ABSTRACT: Atherosclerosis (AS) is a chronic progressive inflammatory disease and a leading cause of death worldwide. Being a novel adipokine, chemerin is reported to be positively correlated with the severity of AS, yet its underlying mechanisms in AS remains elusive. It is well-known that AS development is significantly attributed to abnormal proliferation and migration of vascular smooth muscle cells (VSMCs). Therefore, we investigated the role of the chemerin / chemokine-like receptor 1 (CMKLR1, chemerin receptor) signaling, and the potential therapeutic effect of curcumin in VSMCs proliferation and migration during AS by establishing a high fat diet (HFD) mouse model. We found that CMKLR1 was highly expressed in HFD-induced AS tissues and that its expression level was positively correlated with aortic proliferation. Knockdown of CMKLR1 significantly inhibited VSMCs proliferation and migration, as evidenced by the EdU-incorporation assay, wound healing assay, and the induction of proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase-9 (MMP-9) expression. Furthermore, we discovered that Lipocalin-2 (LCN2) acts as a key factor involved in CMKLR1-mediated VSMCs proliferation and migration via the p38 / MAPK and Wnt / β-catenin signaling pathways, and we demonstrated that curcumin inhibits VSMCs proliferation and migration by inhibiting chemerin / CMKLR1 / LCN2, thereby reducing AS progression. Our findings suggest that chemerin / CMKLR1 activation promotes the development of AS; hence, targeting the chemerin / CMKLR1 / LCN2 signaling pathway may be a reasonable treatment modality for AS.

SUBMITTER: He Y

PROVIDER: S-EPMC8202847 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Curcumin inhibits proliferation, migration and neointimal formation of vascular smooth muscle via activating miR-22.

Project description:Context: Curcumin has antitumor, antioxidative, anti-inflammatory, and anti-proliferative properties.Objective: To investigate the role of miR-22 during curcumin-induced changes in vascular smooth muscle cells (VSMC) and neointima formation in balloon-injured rat abdominal aorta.Materials and methods: Sprague-Dawley rats were randomised to the sham-operated (n = 10), operated control (injured, n = 10), and curcumin treatment (n = 10) groups. miR-22 expression was determined by real-time PCR. SP1 was assessed by western blot and real-time PCR. Rat aortic smooth muscle A7r5 cells were used to determine VSMC proliferation and migration, which were measured by the MTS, EdU staining, Transwell, and wound healing assays.Results: miR-22 levels declined following arterial balloon injury in vivo (48% at 3d, p < 0.05) and serum stimulation in vitro (45% at 24 h, p < 0.01). Functional studies revealed that miR-22 negatively regulated the proliferation and migration of VSMCs by directly targeting the SP1 transcription factor in VSMCs. Curcumin increased the expression of miR-22 (81%, p < 0.05) and decreased the protein expression of SP1 in VSMCs (25%, p < 0.05). miR-22 inhibition was found to attenuate the effects of curcumin on VSMC functions. Curcumin increased miR-22 (46%, p < 0.01), decreased the SP1 protein (19%, p < 0.05), and inhibited vascular neointimal area (48%, p < 0.01) in vivo.Discussion: The miR-22/SP1 pathway is involved in the protective role of curcumin during arterial balloon injury, but the mechanisms remain unclear.Conclusion: miR-22 is involved in the inhibitory effects of curcumin on VSMCs' proliferation, migration and neointima hyperplasia after arterial balloon injury in rats. Curcumin could be used to prevent neointimal hyperplasia after angioplasty.

| S-EPMC8641690 | biostudies-literature

Decorin mimic inhibits vascular smooth muscle proliferation and migration.

Project description:Over the past 10 years, the number of percutaneous coronary intervention procedures performed in the United States increased by 33%; however, restenosis, which inhibits complete functional recovery of the vessel wall, complicates this procedure. A wide range of anti-restenotic therapeutics have been developed, although many elicit non-specific effects that compromise vessel healing. Drawing inspiration from biologically-relevant molecules, our lab developed a mimic of the natural proteoglycan decorin, termed DS-SILY, which can mask exposed collagen and thereby effectively decrease platelet activation, thus contributing to suppression of vascular intimal hyperplasia. Here, we characterize the effects of DS-SILY on both proliferative and quiescent human SMCs to evaluate the potential impact of DS-SILY-SMC interaction on restenosis, and further characterize in vivo platelet interactions. DS-SILY decreased proliferative SMC proliferation and pro-inflammatory cytokine secretion in vitro in a concentration dependent manner as compared to untreated controls. The addition of DS-SILY to in vitro SMC cultures decreased SMC migration and protein synthesis by 95% and 37%, respectively. Furthermore, DS-SILY decreased platelet activation, as well as reduced neointimal hyperplasia by 60%, in vivo using Ossabaw swine. These results indicate that DS-SILY demonstrates multiple biological activities that may all synergistically contribute to an improved treatment paradigm for balloon angioplasty.

| S-EPMC3838406 | biostudies-literature

Chemerin suppresses hepatocellular carcinoma metastasis through CMKLR1-PTEN-Akt axis.

Project description:BackgroundChemerin, a known chemoattractant, participates in multiple biological events. However, its role in cancer remains largely unknown.MethodsChemerin expression was evaluated by real-time PCR, western blot and immunohistochemistry. Forced expression, RNAi, immunoprecipitation, etc. were used in function and mechanism study. Mouse models of extrahepatic and intrahepatic metastasis were employed to evaluate the therapeutic potential of chemerin.ResultsChemerin expression was significantly downregulated in hepatocellular carcinoma, and associated with poor prognosis of HCC patients. Forced expression of chemerin inhibited in vitro migration, invasion and in vivo metastasis of HCC cells. Administration of chemerin effectively suppressed extrahepatic and intrahepatic metastases of HCC cells, resulting in prolonged survival of tumour-bearing nude mice. Chemerin upregulated expression and phosphatase activity of PTEN by interfering with PTEN-CMKLR1 interaction, leading to weakened ubiquitination of PTEN and decreased p-Akt (Ser473) level, which was responsible for suppressed migration, invasion and metastasis of HCC cells. Positive correlation between chemerin and PTEN, and reverse correlation between chemerin and p-Akt (Ser473) were also observed in HCC clinical samples and intrahepatic mouse model in vivo.ConclusionsOur study has revealed the suppressive role and therapeutic potential of chemerin in HCC metastasis, providing both a prognostic marker and drug candidate for HCC.

| S-EPMC5959946 | biostudies-literature

CircMTO1 inhibits ox-LDL-stimulated vascular smooth muscle cell proliferation and migration via regulating the miR-182-5p/RASA1 axis.

Project description:BackgroundCircular RNAs (circRNAs) play critical roles in the development of atherosclerosis (AS). This study investigated the role of circMTO1 in the progression of AS.MethodsSerum samples from AS patients and healthy volunteers and vascular smooth muscle cells (VSMCs) were used as the study materials. The expressions of circMTO1 and miR-182-5p were measured by RT-qPCR. The effects of circMTO1, miR-182-5p, and RASA1 on VSMC proliferation and apoptosis were examined by MTT and BrdU assays and wound healing and flow cytometric analyses, respectively. Downstream target genes of circMTO1 and miR-182-5p were predicted using target gene prediction and screening and confirmed using a luciferase reporter assay. RASA1 expression was detected by RT-qPCR and Western blot.ResultscircMTO1 expression was decreased, while miR-182-5p expression was increased in human AS sera and oxidized low-density lipoprotein (ox-LDL)-stimulated VSMCs. CircMTO1 overexpression inhibited the proliferation and promoted the apoptosis of ox-LDL-stimulated VSMCs. CircMTO1 was found to be served as a sponge of miR-182-5p and RASA1 as a target of miR-182-5p. Moreover, circMTO1 acted as a ceRNA of miR-182-5p to enhance RASA1 expression. Furthermore, miR-182-5p overexpression and RASA1 knockdown reversed the effects of circMTO1 overexpression on the proliferation, migration, and apoptosis of ox-LDL-stimulated VSMCs.ConclusionCircMTO1 inhibited the proliferation and promoted the apoptosis of ox-LDL-stimulated VSMCs by regulating miR-182-5p/RASA1 axis. These results suggest that circMTO1 has potential in AS treatment.

| S-EPMC8268171 | biostudies-literature

Smooth Muscle-Alpha Actin Inhibits Vascular Smooth Muscle Cell Proliferation and Migration by Inhibiting Rac1 Activity.

Project description:Smooth muscle alpha-actin (SMA) is a marker for the contractile, non-proliferative phenotype of adult smooth muscle cells (SMCs). Upon arterial injury, expression of SMA and other structural proteins decreases and SMCs acquire a pro-migratory and proliferative phenotype. To what extent SMA regulates migration and proliferation of SMCs is unclear and putative signaling pathways involved remain to be elucidated. Here, we used lentiviral-mediated gene transfer and siRNA technology to manipulate expression of SMA in carotid mouse SMCs and studied effects of SMA. Overexpression of SMA results in decreased proliferation and migration and blunts serum-induced activation of the small GTPase Rac, but not RhoA. All inhibitory effects of SMA are rescued by expression of a constitutively active Rac1 mutant (V12rac1). Moreover, reduction of SMA expression by siRNA technology results in an increased activation of Rac. Taken together, this study identifies Rac1 as a downstream target for SMA to inhibit SMC proliferation and migration.

| S-EPMC4866761 | biostudies-literature

[Daxx overexpression inhibits Ang?-induced proliferation and migration in vascular smooth muscle cells].

Project description:OBJECTIVE:To construct a recombinant lentiviral expression vector pCDH-Daxx-EGFP to investigate the effect of Daxx on the proliferation of vascular smooth muscle cells (VSMCs). METHODS:The recombinant lentiviral expression vector pCDHDaxx-EGFP was constructed using PCR-based accurate synthesis method. After identification by sequencing and enzyme digestion, the recombinant lentiviral vector was contransfected into 293T cells with lentivirus packaging vector. The recombinant lentivirus particles were collected and purified to infect VSMCs, whose expression of Daxx was detected with Western boltting. The cells infected with the empty vector pCDH-EGFP or pCDH-Daxx-EGFP were incubated in serum-free medium or in the presence of angiotensin ? (Ang?). The cell viability was determined with MTT assay, and the cell cycle changes were analyzed with flow cytometry. The cell migration ability was assessed using a scratch wound healing assay. The expression of p-Akt protein in the cells was detected using Western blotting. RESULTS:Double enzyme digestion and sequencing confirmed successful construction of the recombinant plasmid. Compared with the cells infected with the empty vector, the cells infected with pCDH-Daxx-EGFP exhibited significantly increased expressions of Daxx protein (P < 0.05). Ang? treatment of the cells infected with the pCDH-Daxx-EGFP, as compared with the cells infected with the empty vector, significantly lowered the cell viability, S phase cell ratio and cell migration ability (P < 0.05), and significantly decreased the expression level of p-Akt protein (P < 0.05). CONCLUSIONS:We successfully constructed the recombinant lentiviral vector pCDH-Daxx-EGFP and overexpressed Daxx in primary cultured VSMCs using this vector. Daxx overexpression can inhibit Ang?-induced proliferation and migration in VSMCs probably by regulating p-Akt protein.

| S-EPMC6867952 | biostudies-literature

Luteolin Inhibits Vascular Smooth Muscle Cell Proliferation and Migration by Inhibiting TGFBR1 Signaling.

Project description:Vascular smooth muscle cell (VSMC) proliferation and migration play a critical role in the development of arterial remodeling during various vascular diseases including atherosclerosis, hypertension, and related diseases. Luteolin is a food-derived flavonoid that exerts protective effects on cardiovascular diseases. Here, we investigated whether transforming growth factor-? receptor 1 (TGFBR1) signaling underlies the inhibitory effects of luteolin on VSMC proliferation and migration. We found that luteolin reduced the proliferation and migration of VSMCs, specifically A7r5 and HASMC cells, in a dose-dependent manner, based on MTS and EdU, and Transwell and wound healing assays, respectively. We also demonstrated that it inhibited the expression of proliferation-related proteins including PCNA and Cyclin D1, as well as the migration-related proteins MMP2 and MMP9, in a dose-dependent manner by western blotting. In addition, luteolin dose-dependently inhibited the phosphorylation of TGFBR1, Smad2, and Smad3. Notably, adenovirus-mediated overexpression of TGFBR1 enhanced TGFBR1, Smad2, and Smad3 activation in VSMCs and partially blocked the inhibitory effect of luteolin on TGFBR1, Smad2, and Smad3. Moreover, overexpression of TGFBR1 rescued the inhibitory effects of luteolin on the proliferation and migration of VSMCs. Additionally, molecular docking showed that this compound could dock onto an agonist binding site of TGFBR1, and that the binding energy between luteolin and TGFBR1 was -10.194 kcal/mol. Simulations of molecular dynamics showed that TGFBR1-luteolin binding was stable. Collectively, these data demonstrated that luteolin might inhibit VSMC proliferation and migration by suppressing TGFBR1 signaling.

| S-EPMC6160560 | biostudies-literature

miR-599 Inhibits Vascular Smooth Muscle Cells Proliferation and Migration by Targeting TGFB2.

Project description:Aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) play a crucial role in the pathogenesis of cardiovascular diseases including coronary heart disease, restenosis and atherosclerosis. MicroRNAs are a class of small, non-coding and endogenous RNAs that play critical roles in VSMCs function. In this study, we showed that PDGF-bb, as a stimulant, promoted VSMCs proliferation and suppressed the expression of miR-599. Moreover, overexpression of miR-599 inhibited VSMCs proliferation and also suppressed the PCNA and ki-67 expression. In addition, we demonstrated that ectopic expression of miR-599 repressed the VSMCs migration. We also showed that miR-599 inhibited type I collagen, type V collagen and proteoglycan expression. Furthermore, we identified TGFb2 as a direct target gene of miR-599 in VSMCs. Overexpression of TGFb2 reversed miR-599-induced inhibition of VSMCs proliferation and type I collagen, type V collagen and proteoglycan expression. In conclusion, our findings suggest miR-599 plays a crucial role in controlling VSMCs proliferation and matrix gene expression by regulating TGFb2 expression.

| S-EPMC4638351 | biostudies-literature

Rapamycin inhibits vascular smooth muscle cell migration.

Project description:Abnormal vascular smooth muscle cell (SMC) proliferation and migration contribute to the development of restenosis after percutaneous transluminal coronary angioplasty and accelerated arteriopathy after cardiac transplantation. Previously, we reported that the macrolide antibiotic rapamycin, but not the related compound FK506, inhibits both human and rat aortic SMC proliferation in vitro by inhibiting cell cycle-dependent kinases and delaying phosphorylation of retinoblastoma protein (Marx, S.O., T. Jayaraman, L.O. Go, and A.R. Marks. 1995. Circ. Res. 362:801). In the present study the effects of rapamycin on SMC migration were assayed in vitro using a modified Boyden chamber and in vivo using a porcine aortic SMC explant model. Pretreatment with rapamycin (2 ng/ml) for 48 h inhibited PDGF-induced migration (PDGF BB homodimer; 20 ng/ml) in cultured rat and human SMC (n = 10; P < 0.0001), whereas FK506 had no significant effect on migration. Rapamycin administered orally (1 mg/kg per d for 7 d) significantly inhibited porcine aortic SMC migration compared with control (n = 15; P < 0.0001). Thus, in addition to being a potent immunosuppressant and antiproliferative, rapamycin also inhibits SMC migration.

| S-EPMC507677 | biostudies-other

Notoginsenoside R1 inhibits vascular smooth muscle cell proliferation, migration and neointimal hyperplasia through PI3K/Akt signaling.

Project description:Restenosis caused by neointimal hyperplasia significantly decreases long-term efficacy of percutaneous transluminal angioplasty (PTA), stenting, and by-pass surgery for managing coronary and peripheral arterial diseases. A major cause of pathological neointima formation is abnormal vascular smooth muscle cell (VSMC) proliferation and migration. Notoginsenoside R1 (NGR1) is a novel saponin that is derived from Panax notoginseng and has reported cardioprotective, neuroprotective and anti-inflammatory effects. However, its role in modulating VSMC neointima formation remains unexplored. Herein, we report that NGR1 inhibits serum-induced VSMC proliferation and migration by regulating VSMC actin cytoskeleton dynamics. Using a mouse femoral artery endothelium denudation model, we further demonstrate that systemic administration of NGR1 had a potent therapeutic effect in mice, significantly reducing neointimal hyperplasia following acute vessel injury. Mechanistically, we show that NGR1's mode of action is through inhibiting the activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Taken together, this study identified NGR1 as a potential therapeutic agent for combating restenosis after PTA in cardiovascular diseases.

| S-EPMC5953917 | biostudies-literature

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