• Archives of Pharmacal Research
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• 제29권1호
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• pp.67-72
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• 2006

The abnormal proliferation of aortic vascular smooth muscle cells (VSMCs) plays a central role in the pathogenesis of atherosclerosis and restenosis after angioplasty and possibly also in the development of hypertension. The present study was designed to examine the inhibitory effects and the mechanism of luteolin 7-glucoside (L7G) on the platelet-derived growth factor (PDGF)-BB-induced proliferation of VSMCs. L7G significantly inhibited the PDGF-BB-induced proliferation and the DNA synthesis of the VSMCs in a concentration-dependent manner. Pre-incubation of the VSMCs with L7G significantly inhibited the PDGF-BB-induced extracellular signal-regulated kinase 1/2 (ERK1/2), Akt and the phospholipase C $(PLC)-{\gamma}1$ activation. However, L7G had almost no affect on the phosphorylation of $PDGF-{\beta}$ receptor tyrosine kinase, which was induced by PDGF-BB. These results suggest that L7G inhibits the PDGF-BB-induced proliferation of VSMCs via the blocking of $(PLC)-{\gamma}1$, Akt, and ERK1/2 phosphorylation.

• 한국해양바이오학회지
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• 제10권2호
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• pp.53-61
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• 2018

Sargassum fulvellum (gulfweed) is a widespread seaweed in the coastal areas of northeast Asia. In the present study, we identified the phenolic compounds present in aqueous and ethanolic extracts of S. fulvellum and evaluated their antioxidative properties and their abilities to block cell proliferation using in vitro assays: antioxidant activity was assessed by using a DPPH assay and superoxide anion scavenging activity, anti-tyrosinase activity, and anti-proliferative activity were assessed using MTT and lactate dehydrogenase [LDH] assays in vascular smooth muscle cells. The hot-water ($65^{\circ}C$) extract had a higher phenol content than the ethanolic extract. The hot-water extract showed a statistically significant increase in free radical scavenging activity and a greater ability to reduce proliferation of vascular smooth muscle cells stimulated with platelet-derived growth factor-BB. Taken together, hot-water extracts of S. fulvellum may be an important source of antioxidative and antiproliferative agents.

• Nutrition Research and Practice
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• 제8권5호
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• pp.521-525
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• 2014

BACKGROUND/OBJECTIVES: Artemisinin (AT), an active compound in Arternisia annua, is well known as an anti-malaria drug. It is also known to have several effects including anti-oxidant, anti-inflammation, and anti-cancer activities. To date, the effect of AT on vascular disorders has not been studied. In this study, we investigated the effects of AT on the migration and proliferation of vascular smooth muscle cells (VSMC) stimulated by platelet-derived growth factor BB (PDGF-BB). MATERIALS/METHODS: Aortic smooth muscle cells were isolated from Sprague-Dawley rats. PDGF-BB stimulated VSMC migration was measured by the scratch wound healing assay and the Boyden chamber assay. Cell viability was determined by using an EZ-Cytox Cell Viability Assay Kit. The production of reactive oxygen species (ROS) in PDGF-BB stimulated VSMC was measured through $H_2DCF$-DA staining. We also determined the expression levels of signal proteins relevant to ROS, including measures of extracellular signal-regulated kinase (ERK) 1/2 measured by western blot analysis and matrix metalloproteinase (MMP) 9 measured by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: AT ($10{\mu}M$ and $30{\mu}M$) significantly reduced the proliferation and migration of PDGF-BB stimulated VSMC in a dose-dependent manner. The production of ROS, normally induced by PDGF-BB, is reduced by treatment with AT at both concentrations. PDGF-BB stimulated VSMC treated with AT ($10{\mu}M$ and $30{\mu}M$) have reduced phosphorylation of ERK1/2 and inhibited MMP9 expression compared to untreated PDGF-BB stimulated VSMC. CONCLUSIONS: We suggest, based on these results, that AT may exert an anti-atherosclerotic effect on PDGF-BB stimulated VSMCs by inhibiting their proliferation and migration through down-regulation of ERK1/2 and MMP9 phosphorylation.

• The Korean Journal of Physiology and Pharmacology
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• 제12권4호
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• pp.171-176
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• 2008

Heat shock proteins (HSPs) serve as molecular chaperones and play a role in cell protection from damage in response to stress stimuli. The aim of this article is to investigate whether HSP22 affects IL-8 expression in vascular smooth muscle cells (VSMCs), and which cellular factors are involved in the HSP-mediated IL-8 induction in that cell type in terms of mitogen activated protein kinase (MAPK) and transcription element. Exposure of aortic smooth muscle cells (AoSMCs) to HSP22 not only enhanced IL-8 release but also induced IL-8 transcript via promoter activation. HSP22 activated ERK and p38 MAPK in AoSMCs. HSP22-induced IL-8 release was inhibited by U0126, but not by SB202190. A mutation in the IL-8 promoter region at the binding site of NF-${\kappa}$ B, but not AP-1 or C/EBP, impaired promoter activation in response to HSP22. Delivery of I ${\kappa}$ B, but not dominant negative c-Jun, lowered HSP22-induced IL-8 release from AoSMCs. These results suggest that HS P22 induces IL-8 in VSMCs via ERK1/2, and that transcription factor NF-kB may be required for the HSP22-induced IL-8 up-regulation.

• BMB Reports
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• 제53권4호
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• pp.206-211
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• 2020

Vascular smooth muscle cells (VSMCs) are a unique cell type that has unusual plasticity controlled by environmental stimuli. As an abnormal increase of VSMC proliferation is associated with various vascular diseases, tight regulation of VSMC phenotypes is essential for maintaining vascular homeostasis. Hypoxia is one environmental stress that stimulates VSMC proliferation. Emerging evidence has indicated that microRNAs (miRNAs) are critical regulators in the hypoxic responses of VSMCs. Therefore, we previously investigated miRNAs modulated by hypoxia in VSMCs and found that miR-1260b is one of the most upregulated miRNAs under hypoxia. However, the mechanism that underlies the regulation of VSMCs via miR-1260b in response to hypoxia has not been explored. Here we demonstrated that hypoxia-induced miR-1260b promotes VSMC proliferation. We also identified growth differentiation factor 11 (GDF11), a member of the TGF-β superfamily, as a novel target of miR-1260b. miR-1260b directly targets the 3'UTR of GDF11. Downregulation of GDF11 inhibited Smad signaling and consequently enhanced the proliferation of VSMCs. Our findings suggest that miR-1260b-mediated GDF11-Smad-dependent signaling is an essential regulatory mechanism in the proliferation of VSMCs, and this axis is modulated by hypoxia to promote abnormal VSMC proliferation. Therefore, our study unveils a novel function of miR-1260b in the pathological proliferation of VSMCs under hypoxia.

• Natural Product Sciences
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• 제26권1호
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• pp.71-78
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• 2020

The plant Dendropanax morbifera Léveille is effective folk medicines for the treatment of several conditions, such as infectious diseases, skin diseases, and other illnesses. Although the inhibitory effects of D. morbifera on the proliferation and migration of vascular smooth muscle cells (VSMCs) have been shown in our previous study, its effects in vivo remain to be elucidated. In this study, we aimed to investigate the protective effects of the extracts from D. morbifera (EDM) on neointimal hyperplasia of rat carotid artery and explore the underlying mechanisms. We observed that the ratio of intima to media thickness (I/M) was significantly decreased in the EDM-treated groups by ~80% compared to that of the control. The expression of Ki-67 and proliferating cell nuclear antigen was decreased by ~70% in the EDM-treated groups compared to that of the control. In addition, matrix metalloproteinase (MMP)2 and MMP9 significantly reduced in the neointimal layer of the EDM-treated groups. Moreover, the decreased levels of contractile phenotypic markers of VSMCs, such as α-smooth muscle actin, myocardin, and smooth muscle-myosin heavy chain, were successfully restored by EDM treatment. Furthermore, the levels of synthetic phenotypic markers, cellular retinal binding protein 1 and connexin 43 were also restored to normal levels. These results suggest that EDM inhibits vascular neointimal hyperplasia induced by balloon injury in rats via phenotypic modulation of VSMCs. Therefore, EDM may be a potential drug candidate for the prevention of restenosis.

• The Korean Journal of Physiology and Pharmacology
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• 제7권1호
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• pp.25-28
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• 2003

Ion channel inhibitors are widely used for pharmacological discrimination between the different channel types as well as for determination of their functional role. In the present study, we tested the hypothesis that 4-aminopyridine (4-AP) could affect the large conductance $Ca^{2+}$-activated $K^+$ channel ($BK_{Ca}$) currents using perforated-patch or cell-attached configuration of patch-clamp technique in the rabbit pulmonary arterial smooth muscle. Application of 4-AP reversibly inhibited the spontaneous transient outward currents (STOCs). The reversal potential and the sensitivity to charybdotoxin indicated that the STOCs were due to the activation of $BK_{Ca}$. The $BK_{Ca}$ currents were recorded in single channel resolution under the cell-attached mode of patch-clamp technique for minimal perturbation of intracellular environment. Application of 4-AP also inhibited the single $BK_{Ca}$ currents reversibly and dose-dependently. The membrane potential of rabbit pulmonary arterial smooth muscle cells showed spontaneous transient hyperpolarizations (STHPs), presumably due to the STOC activities, which was also inhibited by 4-AP. These results suggest that 4-AP can inhibit $BK_{Ca}$ currentsin the intact rabbit vascular smooth muscle. The use of 4-AP as a selective voltage-dependent $K^+$ (KV) channel blocker in vascular smooth muscle, therefore, must be reevaluated.

• 생명과학회지
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• 제22권12호
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• pp.1595-1599
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• 2012

혈관 증식 질환에서 세포주기 활성화와 진행은 중요한 치료 목적으로 사용된다. Luteolin는 glycosylated 형태로 샐러리, 후추, 들깨 잎 그리고 카밀레 차에 존재하며 항돌연변이, 항종양, 항산화 그리고 항염증을 나타낸다. 본 연구에서는 흰쥐 동맥으로부터 분리한 혈관평활근세포를 배양하여 소태아혈청으로 유도된 증식에서 luteolin 효과에 대해 조사했다. Luteolin이 5% 소태아혈청으로 유도된 흰쥐의 혈관평활근세포 증식과 DNA 합성을 5, 20 그리고 $50{\mu}M$에서 억제했다. 혈관평활근세포 증식을 각각 29.6, 50.8 그리고 83.1% 억제했고 DNA 합성은 각각 25.8, 57.6 그리고 81.0% 억제했다. 게다가, 유세포분석 결과 소태아혈청으로 유도된 혈관평활근세포의 세포주기는 luteolin에 의해 차단되었다. 이러한 결과는 세포독성에 의해서도 나타날 수 있기 때문에 WST-1 분석으로 세포독성을 확인한 결과 세포독성 없이 세포주기를 차단하는 효과임을 확인했다. 이상의 결과들은 luteolin이 혈관스텐트와 동맥경화의 치료를 위한 의미있는 항증식 물질임을 보여준다.

• 한국식품위생안전성학회지
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• 제26권3호
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• pp.187-191
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• 2011

Platelet derived growth factor (PDGF)-BB is one of the most potent vascular smooth muscle cell(VSMC) proliferative factors, and abnormal VSMC proliferation by PDGF-BB plays an important role in the development and progression of atherosclerosis. The aim of this study was to assess the effect of YP 12, a newly synthesized obovatol derivative, on the proliferation of PDGF-BB-stimulated rat aortic VSMCs. The anti-proliferative effects of YP 12 on rat aortic VSMCs were examined by direct cell counting and by using $[^3H]$ thymidine incorporation assays. It was found that YP 12 potently inhibited the growth of VSMCs. The pre-incubation of YP 12 (1-4 ${\mu}M$) significantly inhibited the proliferation and DNA synthesis of 25 ng/ml PDGF-BB-stimulated rat aortic VSMCs in a concentration-dependent manner. In accordance with these findings, YP 12 revealed blocking of the PDGF-BB-inducible progression through G0/G1 to S phase of the cell cycle in synchronized cells. Whereas, YP 12 did not show any cytotoxicity in rat aortic VSMCs in this experimental condition by WST-1 assay. These results also show that YP 12 may have potential as an anti-proliferative agent for the treatment of restenosis and atherosclerosis.

• 생명과학회지
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• 제16권6호
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• pp.1066-1070
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• 2006

Smooth muscle cell (SMC)의 증식은 혈관성장에 의한 질환의 발병기전의 중요한 요소이다. 혈관 손상 후 SMC의 성장조절에 대한 분자적 기작에 대한 연구는 치료제 개발에 있어 중요한 의미를 지닌다. 이에, 본 연구에서는 TNF family인 RANKL가 SMC의 증식을 촉진함을 입증하였다. RANKL는 p21의 발현을 감소시키고 p21의 promoter활성을 저해함으로써 SMC의 성장을 증가시켰다. 또한 ERK와 p38 MAPK의 활성이 RANKL에 의해 증가하였으며, ERK/p38의 저해제는 RANKL에 의해 유도되는 SMC의 성장을 완전히 억제하였다. 이러한 결과는 ERK와 p38 MAPK가 RANKL에 의해 유도되는 SMC의 증식에 중요한 역할을 함을 보여주는 것이다. 즉, RANK-RANKL-ERK/p38이 SMC의 증식을 매개하는 중요 분자이며, 이들 분자는 혈관 질환을 막는 새로운 치료제 개발의 표적분자가 될 수 있음이 입증되었다.