• The Korean Journal of Physiology and Pharmacology
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• 제19권5호
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• pp.421-426
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• 2015

The increased potential for vascular smooth muscle cell (VSMC) growth is a key abnormality in the development of atherosclerosis and post-angioplasty restenosis. Abnormally high activity of platelet-derived growth factor (PDGF) is believed to play a central role in the etiology of these pathophysiological situations. Here, we investigated the anti-proliferative effects and possible mechanism(s) of murrayafoline A, a carbazole alkaloid isolated from Glycosmis stenocarpa Guillamin (Rutaceae), on PDGF-BB-stimulated VSMCs. Murrayafoline A inhibited the PDGF-BB-stimulated proliferation of VSMCs in a concentration-dependent manner, as measured using a non-radioactive colorimetric WST-1 assay and direct cell counting. Furthermore, murrayafoline A suppressed the PDGF-BB-stimulated progression through $G_0/G_1$ to S phase of the cell cycle, as measured by [$^3H$]-thymidine incorporation assay and cell cycle progression analysis. This anti-proliferative action of murrayafoline A, arresting cell cycle progression at $G_0/G_1$ phase in PDGF-BB-stimulated VSMCs, was mediated via down-regulation of the expression of cyclin D1, cyclin E, cyclin-dependent kinase (CDK)2, CDK4, and proliferating cell nuclear antigen (PCNA), and the phosphorylation of retinoblastoma protein (pRb). These results indicate that murrayafoline A may be useful in preventing the progression of vascular complications such as restenosis after percutaneous transluminal coronary angioplasty and atherosclerosis.

• 동의생리병리학회지
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• 제23권5호
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• pp.974-979
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• 2009

Proliferation of vascular smooth muscle cell(VSMC) is one of the key features in onset of atherosclerosis and restenosis after vascular surgery such as stent implant. Atherosclerotic plaques are usually composed of collagen, elatsin and smooth muscle cells. Release of matrix metalloproteinases(MMPs) is considered to have correlation with development of atherosclerotic plaques. Based on the hypothesis that MMP inhibition would be helpful in the treatment of atherosclerosis, we investigated inhibition of MMP activity and migration of TNF-$\alpha$-induced human aortic smooth muscle cell(HASMC) by Cinnamomi Ramulus(CC). The result from gelatin zymography showed that CC inhibited MMP-9 activity in a dose-dependent manner. In addition, CC considerably inhibited the migration of HASMC induced by TNF-$\alpha$, while it showed little cytotoxic effect on HASMC. These results suggest that CC can be a potential anti-atherosclerotic agent through inhibition of MMP-9 activity and SMC migration.

• 생명과학회지
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• 제28권12호
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• pp.1516-1522
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• 2018

죽상동맥경화는 대동맥의 만성염증에 의해 주로 발병되는 폐쇄동맥질환이다. 혈관평활근세포의 증식 및 이동은 죽상동맥경화 발병의 주된 병리적 반응이다. 본 연구에서는 죽상동맥경화 발병기전을 유도하는 표적 염증반응 물질의 탐색 및 이들에 의한 신호전달 기전을 연구하였다. 혈관평활근세포의 증식 및 이동은 prostaglandin $F_{2{\alpha}}$ ($PGF_{2{\alpha}}$)에 의해 의미 있게 증가하였으나 tumor necrosis factor ${\alpha}$ ($TNF{\alpha}$)에 의해서는 증가하지 않았다. Prostacyclin $I_2$ ($PGI_2$)는 혈관평활근세포의 증식은 촉진시켰으나 이동은 오히려 억제하였다. prostaglandin $D_2$ ($PGD_2$) 및 prostaglandin $E_2$ ($PGE_2$)는 혈관평활근세포의 증식을 촉진시켰으나 이동에는 영향을 미치지 않았다. $PGF_{2{\alpha}}$는 용량 의존적으로 혈관평활근세포의 증식 및 이동을 촉진시켰고 EC50는 약 $0.1{\mu}M$로 관찰되었다. 혈관평활근세포에서 phospholipase $C-{\beta}3$ ($PLC-{\beta}3$) 아형의 발현은 매우 높았으나 $PLC-{\beta}1$, $PLC-{\beta}2$, 및 $PLC-{\beta}4$의 발현은 관찰되지 않았다. U73122 처리를 통해 PLC의 활성을 억제하면 $PGF_{2{\alpha}}$에 의한 혈관평활근세포의 이동이 억제되었다. 또한 $PLC-{\beta}3$의 발현을 억제하면 $PGF_{2{\alpha}}$에 의한 혈관평활근세포의 증식 및 이동이 억제되었다. 이러한 결과들을 바탕으로 $PGF_{2{\alpha}}$ 는 혈관평활근세포의 증식 및 이동에 중요한 역할을 수행하고, 여기에는 $PLC-{\beta}3$가 필수적인 역할을 담당하고 있음을 제안한다.

• BMB Reports
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• 제52권11호
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• pp.665-670
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• 2019

Nucleotide-binding oligomerization domain protein 2 (NOD2), an intracellular pattern recognition receptor, plays important roles in inflammation and cell death. Previously, we have shown that NOD2 is expressed in vascular smooth muscle cells (VSMCs) and that NOD2 deficiency promotes VSMC proliferation, migration, and neointimal formation after vascular injury. However, its role in endoplasmic reticulum (ER) stress-induced cell death in VSMCs remains unclear. Thus, the objective of this study was to evaluate ER stress-induced viability of mouse primary VSMCs. NOD2 deficiency increased ER stress-induced cell death and expression levels of apoptosis mediators (cleaved caspase-3, Bax, and Bak) in VSMCs in the presence of tunicamycin (TM), an ER stress inducer. In contrast, ER stress-induced cell death and expression levels of apoptosis mediators (cleaved caspase-3, Bax, and Bak) were decreased in NOD2-overexpressed VSMCs. We found that the $IRE-1{\alpha}-XBP1$ pathway, one of unfolded protein response branches, was decreased in NOD2-deficient VSMCs and reversed in NOD2-overexpressed VSMCs in the presence of TM. Furthermore, NOD2 deficiency reduced the expression of XBP1 target genes such as GRP78, PDI-1, and Herpud1, thus improving cell survival. Taken together, these data suggest that the induction of ER stress through NOD2 expression can protect against TM-induced cell death in VSMCs. These results may contribute to a new paradigm in vascular homeostasis.