scholarly journals Inhibition of Vascular Smooth Muscle and Cancer Cell Proliferation by New VEGFR Inhibitors and Their Immunomodulator Effect: Design, Synthesis, and Biological Evaluation

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Feng Ran ◽  
Wendong Li ◽  
Yi Qin ◽  
Tong Yu ◽  
Zhao Liu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Tyrosine Kinases ◽  
Active Sites ◽  
Binding Mode ◽  
Inhibitory Effect ◽  
Biological Evaluation ◽  
Active Member ◽  
Vsmc Proliferation

Abnormal vascular smooth muscle cell (VSMC) proliferation has an important role in the pathogenesis of both atherosclerosis restenosis and hypertension. Vascular endothelial growth factor (VEGF) has been shown to stimulate VSMC proliferation. In addition, angiogenesis is one of the hallmarks of cancerous growth. VEGF is the key modulator for the initial stages of angiogenesis that acts through the endothelial-specific receptor tyrosine kinases (VEGFRs). VEGFR-2 blockage is a good approach for suppression of angiogenesis. In order to discover novel VEGFR-2 TK inhibitors, we have designed and synthesized three new series of pyridine-containing compounds. The new compounds were all screened against a panel of three cell lines (HepG-2, HCT-116, and MCF-7). Promising results encouraged us to additionally evaluate the most active members for their in vitro VEGFR-2 inhibitory effect. Compound 7a, which is the most potent candidate, revealed a significant increase in caspase-3 level by 7.80-fold when compared to the control. In addition, Bax and Bcl-2 concentration levels showed an increase in the proapoptotic protein Bax (261.4 Pg/ml) and a decrease of the antiapoptotic protein Bcl-2 (1.25 Pg/ml) compared to the untreated cells. Furthermore, compound 7a arrested the cell cycle in the G2/M phase with induction of apoptosis. The immunomodulatory effect of compound 7a, the most active member, showed a reduction in TNF-α by 87%. Also, compound 7a caused a potent inhibitory effect on smooth muscle proliferation. Docking studies were also performed to get better insights into the possible binding mode of the target compounds with VEGFR-2 active sites.

scholarly journals Geranylgeranyl Transferase-I Knockout Inhibits Oxidative Injury of Vascular Smooth Muscle Cells and Attenuates Diabetes-Accelerated Atherosclerosis

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Guo-Ping Chen ◽  
Jian Yang ◽  
Guo-Feng Qian ◽  
Wei-Wei Xu ◽  
Xiao-Qin Zhang
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
High Glucose ◽  
Oxidative Injury ◽  
Accelerated Atherosclerosis ◽  
Vsmc Proliferation ◽  
Geranylgeranyl Transferase

The proliferation of vascular smooth muscle cells (VSMCs) induced by oxidative injury is one of the main features in diabetes-accelerated atherosclerosis. Geranylgeranyl transferase-I (GGTase-I) is an essential enzyme mediating posttranslational modification, especially the geranylgeranylation of small GTPase, Rac1. Our previous studies found that GGTase-I played an important role in diabetes-accelerated atherosclerosis. However, its exact role is largely unclear. In this study, mouse conditional knockout of VSMC GGTase-I (Pggt1bΔ/Δ mice) was generated using the CRISPR/Cas9 system. The mouse model of diabetes-accelerated atherosclerosis was induced by streptozotocin injections and an atherogenic diet. We found that GGTase-I knockout attenuated diabetes-accelerated atherosclerosis in vivo and suppressed high-glucose-induced VSMC proliferation in vitro. Moreover, after a 16-week duration of diabetes, Pggt1bΔ/Δ mice exhibited lower α-smooth muscle actin (α-SMA) and nitrotyrosine level, Rac1 activity, p47phox and NOXO1 expression, and phospho-ERK1/2 and phosphor-JNK content than wild-type mice. Meanwhile, the same changes were found in Pggt1bΔ/Δ VSMCs cultured with high glucose (22.2 mM) in vitro. In conclusion, GGTase-I knockout efficiently blocked diabetes-accelerated atherosclerosis, and this protective effect must be related to the inhibition of VSMC proliferation. The potential mechanisms probably involved interfering Rac1 geranylgeranylation, inhibiting the assembly of NADPH oxidase cytosolic regulatory subunits, reducing oxidative injury, and decreasing ERK1/2 and JNK phosphorylation.

scholarly journals Inhibitory effect of D1-like and D3 dopamine receptors on norepinephrine-induced proliferation in vascular smooth muscle cells

2008 ◽  
Vol 294 (6) ◽  
pp. H2761-H2768 ◽  
Author(s):  
Zhen Li ◽  
Changqing Yu ◽  
Yu Han ◽  
Hongmei Ren ◽  
Weibin Shi ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Adrenergic Receptor ◽  
Receptor Agonist ◽  
Thymidine Incorporation ◽  
Inhibitory Effect ◽  
Vsmc Proliferation

The sympathetic nervous system plays an important role in the regulation of blood pressure. There is increasing evidence for positive and negative interactions between dopamine and adrenergic receptors; the activation of the α-adrenergic receptor induces vasoconstriction, whereas the activation of dopamine receptor induces vasorelaxation. We hypothesize that the D1-like receptor and/or D3 receptor also inhibit α1-adrenergic receptor-mediated proliferation in vascular smooth muscle cells (VSMCs). In this study, VSMC proliferation was determined by measuring [3H]thymidine incorporation, cell number, and uptake of 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT). Norepinephrine increased VSMC number and MTT uptake, as well as [3H]thymidine incorporation via the α1-adrenergic receptor in aortic VSMCs from Sprague-Dawley rats. The proliferative effects of norepinephrine were attenuated by the activation of D1-like receptors or D3 receptors, although a D1-like receptor agonist, fenoldopam, and a D3 receptor agonist, PD-128907, by themselves, at low concentrations, had no effect on VSMC proliferation. Simultaneous stimulation of both D1-like and D3 receptors had an additive inhibitory effect. The inhibitory effect of D3 receptor was via protein kinase A, whereas the D1-like receptor effect was via protein kinase C-ζ. The interaction between α1-adrenergic and dopamine receptors, especially D1-like and D3 receptors in VSMCs, could be involved in the pathogenesis of hypertension.

scholarly journals Nogo-B Receptor Directs Mitochondria-Associated Membranes to Regulate Vascular Smooth Muscle Cell Proliferation

2019 ◽  
Vol 20 (9) ◽  
pp. 2319
Author(s):  
Yi-Dong Yang ◽  
Man-Man Li ◽  
Gang Xu ◽  
Lan Feng ◽  
Er-Long Zhang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Nuclear Localization ◽  
Epithelial Mesenchymal Transition ◽  
Pulmonary Arteries ◽  
Underlying Mechanism ◽  
Mesenchymal Transition ◽  
Vsmc Proliferation ◽  
Vsmcs Proliferation

Mitochondria-associated membranes (MAM) are a well-recognized contact link between the mitochondria and endoplasmic reticulum that affects mitochondrial biology and vascular smooth muscle cells (VSMCs) proliferation via the regulation of mitochondrial Ca2+(Ca2+m) influx. Nogo-B receptor (NgBR) plays a vital role in proliferation, epithelial-mesenchymal transition, and chemoresistance of some tumors. Recent studies have revealed that downregulation of NgBR, which stimulates the proliferation of VSMCs, but the underlying mechanism remains unclear. Here, we investigated the role of NgBR in MAM and VSMC proliferation. We analyzed the expression of NgBR in pulmonary arteries using a rat model of hypoxic pulmonary hypertension (HPH), in which rats were subjected to normoxic recovery after hypoxia. VSMCs exposed to hypoxia and renormoxia were used to assess the alterations in NgBR expression in vitro. The effect of NgBR downregulation and overexpression on VSMC proliferation was explored. The results revealed that NgBR expression was negatively related with VSMCs proliferation. Then, MAM formation and the phosphorylation of inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) was detected. We found that knockdown of NgBR resulted in MAM disruption and augmented the phosphorylation of IP3R3 through pAkt, accompanied by mitochondrial dysfunction including decreased Ca2+m, respiration and mitochondrial superoxide, increased mitochondrial membrane potential and HIF-1α nuclear localization, which were determined by confocal microscopy and Seahorse XF-96 analyzer. By contrast, NgBR overexpression attenuated IP3R3 phosphorylation and HIF-1α nuclear localization under hypoxia. These results reveal that dysregulation of NgBR promotes VSMC proliferation via MAM disruption and increased IP3R3 phosphorylation, which contribute to the decrease of Ca2+m and mitochondrial impairment.

Abstract 374: Inhibition of Mitochondrial CaMKII Reduces Vascular Smooth Muscle Migration and Neointima Formation and Halts Mitochondrial Mobility

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Emily Nguyen ◽  
Olha Koval ◽  
Isabella Grumbach
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Mitochondrial Fission ◽  
Leading Edge ◽  
Neointima Formation ◽  
Vsmc Proliferation ◽  
Mitochondrial Motility ◽  
And Migration

Background: Restenosis after angioplasty for coronary vascular disease remains a critical problem in cardiovascular medicine. Vascular smooth muscle cell (VSMC) migration and proliferation cause restenosis through neointima formation. Mitochondrial motility is likely necessary for cell proliferation and migration, and is inhibited in microdomains with increased Ca 2+ . The Ca 2+ /calmodulin-dependent kinase II (CaMKII) in mitochondria (mtCaMKII) is proposed to control mitochondrial matrix Ca 2+ uptake through mitochondrial Ca 2+ uniporter (MCU). Thus, we hypothesized that blocking mtCaMKII decreases VSMC migration and neointima formation by decreasing mitochondrial motility. Methods: mtCaMKII was inhibited by expression of the mitochondria-targeted CaMKII inhibitor peptide (CaMKIIN) in a novel transgenic mouse model in smooth muscle only (SM-mtCaMKIIN) or delivered by adenoviral transduction (Ad-mtCaMKIIN). Results: In our models, mtCaMKIIN was detected selectively in mitochondria of VSMC. mtCaMKIIN significantly reduced mitochondrial Ca 2+ current and Ca 2+ content compared to WT in vivo and in vitro. SM-mtCaMKIIN mice showed significantly reduced neointimal area 28 days after endothelial injury (n=8, p<0.05) and fewer proliferating neointimal cells by PCNA staining. In vitro, Ad-mtCaMKIIN mildly reduced VSMC proliferation and mitochondrial ROS production without altering maximal respiration after PDGF treatment. Ad-mtCaMKIIN abolished VSMC migration, as did mitoTEMPO and MCU inhibitor Ru360. Ad-mtCaMKIIN blocked mitochondrial mobility towards the leading edge, while relocation of mitochondria was seen in WT cells 6 h after PDGF treatment. Mitochondrial redistribution was also inhibited by Ru360, but not by mitoTEMPO or cytoplasmic CaMKII inhibition. Mitochondrial fission promotes cell migration. Accordingly, PDGF increased mitochondrial particles in WT VSMC, while mitochondria in Ad-mtCaMKIIN cells were fragmented and unresponsive to PDGF treatment. Conclusions: mtCaMKIIN prevents mitochondrial distribution to the leading edge and reduces VSMC migration and neointima formation. These data suggest mitochondrial Ca 2+ regulation plays an important role in VSMC migration by altering mitochondrial location.

scholarly journals Salusin-α Inhibits Proliferation and Migration of Vascular Smooth Muscle Cell via Akt/mTOR Signaling

2018 ◽  
Vol 50 (5) ◽  
pp. 1740-1753 ◽  
Author(s):  
Shoucui Gao ◽  
Liran Xu ◽  
Yali Zhang ◽  
Qingqing Yu ◽  
Jiayan Li ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Atherosclerotic Lesion ◽  
Cell Counting ◽  
Matrix Metalloproteinase 2 ◽  
Aortic Lesion ◽  
Vsmc Proliferation ◽  
And Migration ◽  
Proliferation And Migration

Background/Aims: The proliferation and migration of vascular smooth muscle cells (VSMCs) are key steps in the progression of atherosclerosis. The aim of the present study was to investigate the potential roles of salusin-α in the functions of VSMCs during the development of atherosclerosis. Methods: In vivo, the effects of salusin-α on atherogenesis were examined in rabbits fed a cholesterol diet. The aortas were en face stained with Sudan IV to evaluate the gross atherosclerotic lesion size. The cellular components of atherosclerotic plaques were analyzed by immunohistochemical methods. In vitro, Cell Counting Kit-8 and wound-healing assays were used to assess the effects of salusin-α on VSMC proliferation and migration. In addition, western blotting was used to evaluate the total and phosphorylated levels of Akt (also known as protein kinase B) and mammalian target of rapamycin (mTOR) in VSMCs. Results: Salusin-α infusion significantly reduced the aortic lesion areas of atherosclerosis, with a 39% reduction in the aortic arch, a 71% reduction in the thoracic aorta, and a 71% reduction in the abdominal aorta; plasma lipid levels were unaffected. Immunohistochemical staining showed that salusin-α decreased both macrophage- and VSMC-positively stained areas in atherosclerotic lesions by 54% and 69%, cell proliferative activity in the intima and media of arteriosclerotic lesions, and matrix metalloproteinase 2 (MMP-2) and MMP-9 expression in plaques. Studies using cultured VSMCs showed that salusin-α decreased VSMC migration and proliferation via reduced phosphorylation of Akt and mTOR. Conclusion: Our data indicate that salusin-α suppresses the development of atherosclerosis by inhibiting VSMC proliferation and migration through the Akt/mTOR pathway.

Inhibition of vascular smooth muscle cell proliferation by chronic hemin treatment

2008 ◽  
Vol 295 (3) ◽  
pp. H999-H1007 ◽  
Author(s):  
Tuanjie Chang ◽  
Lingyun Wu ◽  
Rui Wang
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Cell Cycle Progression ◽  
Control Level ◽  
Inhibitory Effect ◽  
Cycle Progression ◽  
Vsmc Proliferation ◽  
Long Term Treatment

Hemin, an oxidized form of heme, is an essential regulator of gene expression and cell cycle progression. Our laboratory previously reported ( 34 ) that chronic hemin treatment of spontaneously hypertensive rats reversed the eutrophic inward remodeling of small peripheral arteries. Whether long-term treatment of cultured vascular smooth muscle cells (VSMCs) with hemin alters the proliferation status of these cells has been unknown. In the present study, hemin treatment at 5 μM for 4, 7, 14, and 21 days significantly inhibited the proliferation of cultured rat aortic VSMCs (A-10 cells) by arresting cells at G0/G1 phases so as to decelerate cell cycle progression. Heme oxygenase (HO) activity and inducible HO-1 protein expression were significantly increased by hemin treatment. HO inhibitor tin protoporphyrin IX (SnPP) abolished the effects of hemin on cell proliferation and HO activity. Interestingly, hemin-induced HO-1 expression was further increased in the presence of SnPP. Hemin treatment had no significant effect on the expression of constitutive HO-2. Expression of p21 protein and the level of reactive oxygen species (ROS) were decreased by hemin treatment, which was reversed by application of SnPP. After removal of hemin from culture medium, inhibited cell proliferation and increased HO-1 expression in VSMCs were returned to control level within 1 wk. Transfection with HO-1 small interfering RNA significantly knocked down HO-1 expression and decreased HO activity, but had no effect on HO-2 expression, in cells treated with or without hemin for 7 days. The inhibitory effect of hemin on cell proliferation was abolished in HO-1 silenced cells. It is concluded that induction of HO-1 and, consequently, increased HO activity are responsible for the chronic inhibitory effect of hemin on VSMC proliferation. Changes in the levels of p21 and ROS might also participate in the cellular effects of hemin.

Differential regulation of vascular smooth muscle and endothelial cell proliferation in vitro and in vivo by cAMP/PKA-activated p85αPI3K

2009 ◽  
Vol 297 (6) ◽  
pp. H2015-H2025 ◽  
Author(s):  
Daniele Torella ◽  
Cosimo Gasparri ◽  
Georgina M. Ellison ◽  
Antonio Curcio ◽  
Angelo Leone ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Neointimal Hyperplasia ◽  
Endothelial Cell Proliferation ◽  
Balloon Injury ◽  
Vsmc Proliferation ◽  
Endothelial Regeneration ◽  
Proliferation In Vitro

cAMP inhibits proliferation in most cell types, triggering different and sometimes opposing molecular pathways. p85α (phosphatidylinositol 3-kinase regulatory subunit) is phosphorylated by cAMP/PKA in certain cell lineages, but its effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) are unknown. In the present study, we evaluated 1) the role of p85α in the integration of cAMP/PKA-dependent signaling on the regulation of VSMC and EC growth in vitro; and 2) the effects of PKA-modified p85α on neointimal hyperplasia and endothelial healing after balloon injury in vivo. Plasmid constructs carrying wild-type and PKA-modified p85α were employed in VSMCs and ECs in vitro and after balloon injury in rat carotid arteries in vivo. cAMP/PKA reduced VSMC proliferation through p85α phosphorylation. Transfected PKA-activated p85α binds p21ras, reducing ERK1/2 activation and VSMC proliferation in vitro. In contrast, EC proliferation inhibition by cAMP is independent from PKA modification of p85α and ERK1/2 inhibition; indeed, PKA-activated p85α did not inhibit per se ERK1/2 activation and proliferation in ECs in vitro. Interestingly, cAMP reduced both VSMC and EC apoptotic death through p85α phosphorylation. Accordingly, PKA-activated p85α triggered Akt activation, reducing both VSMC and EC apoptosis in vitro. Finally, compared with controls, vascular gene transfer of PKA-activated p85α significantly reduced neointimal formation after balloon injury in rats, without inhibiting endothelial regeneration of the injured arterial segment. In conclusions, PKA-activated p85α integrates cAMP/PKA signaling differently in VSMCs and ECs. By reducing neointimal hyperplasia without inhibiting endothelial regeneration, it exerts a protective effect against restenosis after balloon injury.

Abstract 459: O-Linked N-Acetylglucosamine Promotes Vascular Smooth Muscle Cell Dedifferentiation and Intimal Hyperplasia

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Ashley J Bauer ◽  
Kristen L Leslie ◽  
Allison C Ostriker ◽  
Kathleen A Martin
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Intimal Hyperplasia ◽  
Transcriptional Repression ◽  
Human Coronary Artery ◽  
Artery Ligation ◽  
Vsmc Proliferation ◽  
Marker Expression

Vascular smooth muscle cells (VSMCs) exhibit a unique phenotypic plasticity that underlies numerous cardiovascular pathologies. Platelet-derived growth factor (PDGF) promotes VSMC dedifferentiation characterized by proliferation and decreased contractile protein expression while the mTORC1 inhibitor and stent therapeutic rapamycin inhibits these effects. The enzyme O-linked N-Acetylglucosamine (O-GlcNAc) Transferase (OGT) adds O-GlcNAc modifications to serine or threonine in proteins and has been implicated in cardiovascular diseases. We hypothesized that OGT may regulate VSMC plasticity. We found that OGT and O-GlcNAc expression were associated with dedifferentiation, as both were decreased by rapamycin, but increased with PDGF treatment in human coronary artery SMCs. Knocking down OGT in vitro increased contractile marker expression at the mRNA and protein levels, including MYH11, CNN, TGLN, and ACTA2, while decreasing VSMC proliferation. Conversely, OGT overexpression inhibited expression of MHY11, CNN, and TGLN. Consistent with a role in dedifferentiation, immunostaining revealed that OGT and O-GlcNAc were increased following femoral artery endothelial denudation injury in C57BL/6 mice. Notably, smooth muscle-specific OGT knockout attenuated neointima formation relative to controls in a carotid artery ligation model of intimal hyperplasia. In conclusion, these findings indicate that PDGF and vascular injury increase OGT expression and O-GlcNAc modifications in SMCs in vitro and in vivo, leading to OGT-dependent transcriptional repression of contractile marker expression and promotion of intimal hyperplasia.

Abstract 446: EphA2 Regulates Vascular Smooth Muscle Fibroproliferative Remodeling in Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Alexandra C Finney ◽  
Jonette M Green ◽  
Mohammad A Rana ◽  
Steven D Funk ◽  
James G Traylor ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Knockout Mice ◽  
Tyrosine Kinases ◽  
Atherosclerotic Plaques ◽  
Eph Receptors ◽  
Matrix Deposition ◽  
Enhanced Expression

Eph receptors, the largest mammalian subfamily of receptor tyrosine kinases, regulate inflammation and tissue remodeling. The EphA2 receptor shows enhanced expression in atherosclerosis, and deletion of EphA2 in atherosclerosis-prone ApoE knockout mice attenuates lesion formation. We now show that EphA2 knockout mice exhibit reduced late stage plaque progression associated with diminished smooth muscle content. While EphA2 is absent in quiescent vascular smooth muscle cells in vitro and in vivo , dedifferentiation to a synthetic phenotype significantly upregulates EphA2 expression. Deletion of EphA2, a known oncogene, reduces markers of proliferation in atherosclerotic plaques, and EphA2 knockdown similarly reduces vascular smooth muscle proliferation in culture with associated reductions in serum-induced ERK and Akt signaling. In addition to proliferation, EphA2 knockout mice show significantly reduced collagen content in their atherosclerotic plaques, and EphA2 knockdown reduces smooth muscle matrix deposition in vitro . Together these data suggest a potential role for EphA2 in smooth-muscle driven vascular fibroproliferative remodeling, representing the first link between EphA2 signaling and smooth muscle function.

The indazole derivative YD-3 inhibits thrombin-induced vascular smooth muscle cell proliferation and attenuates intimal thickening after balloon injury

2004 ◽  
Vol 92 (12) ◽  
pp. 1232-1239 ◽  
Author(s):  
Jih-Hwa Guh ◽  
Yi-Nan Liu ◽  
Ya-Ling Chang ◽  
Sheng-Chu Kuo ◽  
Fang-Yu Lee ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Developmental Potential ◽  
Vsmc Proliferation ◽  
Neointimal Thickness ◽  
Immunochemical Detection

SummaryProliferation of vascular smooth muscle cells (VSMCs) is postulated to be one of the key events in the pathogenesis of atherosclerosis and restenosis. We investigated whether YD-3, a lowmolecular weight, non-peptide compound, could modulate proliferation of VSMCs in vitro and restenosis after balloon angioplasty in vivo. We examined the effect of YD-3 on thrombininduced VSMC proliferation by [3H]thymidine incorporation assay. The data demonstrated that YD-3 inhibited VSMC proliferation in a concentration-dependent manner. To define the mechanisms of YD-3 action, we found that YD-3 showed a profound inhibition on thrombin-induced Ras and ERK1/2 activities by using Western blotting analysis. Furthermore, oral administration of YD-3 exhibited a marked reduction in neointimal thickness using the carotid injury model in rats. Using immunochemical detection, our experiments also revealed that YD-3 significantly suppressed expression of the PAR-1 receptor, and markedly inhibited PAR-1-activating peptide (SFLLRN)-induced VSMC proliferation in a concentration-dependent manner. These results suggest that YD-3 inhibits thrombin-induced VSMC growth via the Rasand ERK1/2-mediated signaling pathway. Moreover, YD-3 also shows a developmental potential in the treatment of atherosclerosis and restenosis after vascular injury.

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