scholarly journals JANEX-1 improves acute pulmonary embolism through VEGF and FAK in pulmonary artery smooth muscle cells

2020 ◽  
Vol 245 (15) ◽  
pp. 1395-1403
Author(s):  
Longfei Pan ◽  
Zhuo Peng ◽  
Ruipeng Zhang ◽  
Rui Zhang ◽  
Dean Liang ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Acute Pulmonary Embolism ◽  
Janus Kinase ◽  
Vegf Expression ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Janus Kinase 3

Although clinical treatment has significant progress, acute pulmonary embolism is still a common disease with high morbidity and mortality. Janus Kinase 3, a member of JAK family, has been demonstrated to promote smooth muscle cell proliferation through STAT3. In this work, we explored the effect of JANEX-1 (a specific Janus Kinase 3 inhibitor) on platelet-derived growth factor (PDGF)-induced proliferation-related molecules in pulmonary artery smooth muscle cells (PVSMCs) in vitro and assessed the therapeutic potential of Janus Kinase 3 for vascular remodeling in acute pulmonary embolism mice. The results revealed that Janus Kinase 3 was overexpressed and active in PDGF-induced PVSMCs and acute pulmonary embolism mice, compared to a low expression in normal conditions. JANEX-1, blocking Janus Kinase 3 expression or activity, reduced Janus Kinase 3/STAT3 signaling pathway, VEGF expression, FAK activation, and PDGF-induced proliferation of PVSMCs, while overexpression of VEGF or FAK induced PVSMCs proliferation and resisted the negative effects of JANEX-1. Moreover, JANEX-1 improved right ventricular systolic pressure, survival and lung damage in acute pulmonary embolism-mice, and inhibited the thrombus-induced intimal hyperplasia and the expression of α-SMA, VEGF, and FAK activation under neointimal smooth muscle cells of acute pulmonary embolism mice. In conclusion, the data suggest that JANEX-1 exerts protective effects by inhibiting PVSMCs proliferation and vascular remodeling post-acute pulmonary embolism, in part through Janus Kinase 3/STAT3 signaling pathway-mediated VEGF expression and FAK activation. The data are helpful to elucidate the pharmacological mechanism and potential therapeutic effect of JANEX-1 in APE. Impact statement Accumulating evidence suggests that vascular remodeling due to immoderate proliferation and migration of SMCs is a common process occurring in APE. In this work, we tried to find a breakthrough in the pathological mechanism to alleviate the prognosis of APE by improving SMCs proliferation and explored the effect of JANEX-1 on PDGF-induced proliferation-related molecules in PVSMCs and assessed the therapeutic potential of JAK3 for vascular remodeling in APE mice. We demonstrated that JANEX-1, blocking JAK3 expression or activity, reduced JAK3/STAT3 signaling pathway, VEGF expression and FAK activation, and PDGF-induced proliferation of PVSMCs. Moreover, JANEX-1 inhibited the thrombus-induced intimal hyperplasia and the expression of VEGF and FAK activation in neointimal SMCs of APE mice. The data are helpful to elucidate the pharmacological mechanism and potential therapeutic effect of JANEX-1 in APE.

Janus Kinase 3 Deficiency Promotes Vascular Reendothelialization

2021 ◽  
Author(s):  
Yung-Chun Wang ◽  
Dunpeng Cai ◽  
Xiao-Bing Cui ◽  
Ya-Hui Chuang ◽  
William P. Fay ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Injury ◽  
Intimal Hyperplasia ◽  
Carotid Arteries ◽  
Muscle Cells ◽  
Janus Kinase ◽  
Balloon Injury ◽  
Janus Kinase 3

Objective: The objective of this study is to determine the role of JAK3 (Janus kinase 3) in reendothelialization after vascular injury. Methods and Results: By using mouse carotid artery wire injury and rat balloon injury model, we found that JAK3 regulates reendothelialization and endothelial cell proliferation after vascular injury. JAK3 and phospho-JAK3 levels were increased in neointimal smooth muscle cells in response to vascular injury in mice. JAK3 deficiency dramatically attenuated the injury-induced intimal hyperplasia in carotid arteries of both male and female mice. Importantly, JAK3 deficiency caused an increased rate of reendothelialization following mechanical injury. Likewise, knockdown of JAK3 in medial smooth muscle cells elicited an accelerated reendothelialization with reduced intimal hyperplasia following balloon injury in rat carotid arteries. Interestingly, knockdown of JAK3 restored the expression of smooth muscle cell contractile protein smooth muscle α-actin in injury-induced intimal smooth muscle cells while increased the proliferating endothelial cells in the intima area. Conclusions: Our results demonstrate a novel role of JAK3 in the regeneration of endothelium after vascular injury, which may provide a new strategy to enhance reendothelialization while suppressing neointimal formation for effective vascular repair from injury.

Abstract 521: Janus Kinase 3 is a Novel Regulator for Smooth Muscle Proliferation and Vascularremodeling

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Yung-Chun Wang
Keyword(s):  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Ectopic Expression ◽  
Specific Inhibitor ◽  
Vascular Diseases ◽  
Janus Kinase ◽  
Nuclear Antigen ◽  
Neointima Formation ◽  
Janus Kinase 3

Vascular remodeling due to smooth muscle cell (SMC) proliferation is a common process occurring in a number of vascular diseases such as atherosclerosis, aortic aneurysm, posttransplant vasculopathy, and restenosis after angioplasty, etc. The molecular mechanism underlying SMC proliferation, however, is not completed understood. Our present study has identified Janus kinase 3 (JAK3), a member of the Janus kinase family, as a novel regulator for SMC proliferation. Platelet-derived growth factor (PDGF)-BB, a SMC mitogen, induces JAK3 expression and phosphorylation while stimulating SMC proliferation. Janex-1, a specific inhibitor of JAK3, or knockdown of JAK3 by shRNA inhibits SMC proliferation. Conversely, ectopic expression of JAK3 promotes SMC proliferation. Interestingly, JAK3 does not affect SMC contractile protein expression, suggesting that JAK3 mediate the proliferation, but not the phenotypic modulation of SMC. Mechanistically, JAK3 promotes SMC proliferation by regulating phosphorylation of Signal transducer and activator of transcription 3 and c-Jun N-terminal kinase. In vivo, by using a rat carotid balloon-injury model, we found that knockdown of JAK3 significantly attenuates injury-induced neointima formation. Importantly, JAK3 knockdown blocked the expression of proliferating cell nuclear antigen, suggesting that JAK3 is essential for SMC proliferation in vivo. Moreover, JAK3 knockdown prompts apoptosis in neointima SMC, indicating that JAK3 also stimulates SMC survival during neointima formation. Collectively, our data demonstrate that JAK3 mediates vascular remodeling by promoting both the SMC proliferation and survival.

scholarly journals Adenosine upregulates VEGF expression in cultured myocardial vascular smooth muscle cells

1999 ◽  
Vol 277 (2) ◽  
pp. H595-H602 ◽  
Author(s):  
Jian-Wei Gu ◽  
Ann L. Brady ◽  
Vivek Anand ◽  
Michael C. Moore ◽  
Whitney C. Kelly ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Mrna Expression ◽  
Vascular Smooth Muscle Cells ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Protein Levels ◽  
Hypoxic Conditions ◽  
Vegf Mrna Expression ◽  
Vegf Protein

We tested whether adenosine has differential effects on vascular endothelial growth factor (VEGF) expression under normoxic and hypoxic conditions, and whether A1 or A2 receptors (A1R; A2R) mediate these effects. Myocardial vascular smooth muscle cells (MVSMCs) from dog coronary artery were exposed to hypoxia (1% O2) or normoxia (20% O2) in the absence and presence of adenosine agonists or antagonists for 18 h. VEGF protein levels were measured in media with ELISA. VEGF mRNA expression was determined with Northern blot analysis. Under normoxic conditions, the adenosine A1R agonists, N 6-cyclopentyladenosine and R(-)- N 6-(2-phenylisopropyl)adenosine did not increase VEGF protein levels at A1R stimulatory concentrations. However, adenosine (5 μM) and the adenosine A2R agonist N 6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)]ethyl adenosine (DPMA; 100 nM) increased VEGF protein levels by 51 and 132% and increased VEGF mRNA expression by 44 and 90%, respectively, in cultured MVSMCs under normoxic conditions. Hypoxia caused an approximately fourfold increase in VEGF protein and mRNA expression, which could not be augmented with exogenous adenosine, A2R agonist (DPMA), or A1R agonist [1,3-diethyl-8-phenylxanthine (DPX)]. The A2R antagonist 8-(3-chlorostyryl)-caffeine completely blocked adenosine-induced VEGF protein and mRNA expression and decreased baseline VEGF protein levels by up to ∼60% under normoxic conditions but only by ∼25% under hypoxic conditions. The A1R antagonist DPX had no effect. These results are consistent with the hypothesis that 1) adenosine increases VEGF protein and mRNA expression by way of A2R. 2) Adenosine plays a major role as an autocrine factor regulating VEGF expression during normoxic conditions but has a relatively minor role during hypoxic conditions. 3) Endogenous adenosine can account for the majority of basal VEGF secretion by MVSMCs under normoxic conditions and could therefore be a maintenance factor for the vasculature.

scholarly journals Long Non-Coding RNA MEG3 Downregulation Triggers Human Pulmonary Artery Smooth Muscle Cell Proliferation and Migration via the p53 Signaling Pathway

2017 ◽  
Vol 42 (6) ◽  
pp. 2569-2581 ◽  
Author(s):  
Zengxian Sun ◽  
Xiaowei Nie ◽  
Shuyang Sun ◽  
Shumin Dong ◽  
Chunluan Yuan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Remodeling ◽  
Pulmonary Artery Smooth Muscle ◽  
And Migration ◽  
Proliferation And Migration

Background/Aims: Increasing evidence has demonstrated a significant role of long non-coding RNAs (lncRNAs) in diverse biological processes, and many of which are likely to have functional roles in vascular remodeling. However, their functions in pulmonary arterial hypertension (PAH) remain largely unknown. Pulmonary vascular remodeling is an important pathological feature of PAH, leading to increased vascular resistance and reduced compliance. Pulmonary artery smooth muscle cells (PASMCs) dysfunction is involved in vascular remodeling. Long noncoding RNAs are potential regulators of PASMCs function. Herein, we determined whether long noncoding RNA–maternally expressed gene 3 (MEG3) was involved in PAH-related vascular remodeling. Methods: The arterial wall thickness was examined by hematoxylin and eosin (H&E) staining in distal pulmonary arteries (PAs) isolated from lungs of healthy volunteers and PAH patients. The expression level of MEG3 was analyzed by qPCR. The effects of MEG3 on human PASMCs were assessed by cell counting Kit-8 assay, BrdU incorporation assay, flow cytometry, scratch-wound assay, immunofluorescence, and western blotting in human PASMCs. Results: We revealed that the expression of MEG3 was significantly downregulated in lung and PAs of patients with PAH. MEG3 knockdown affected PASMCs proliferation and migration in vitro. Moreover, inhibition of MEG3 regulated the cell cycle progression and made more smooth muscle cells from the G0/G1 phase to the G2/M+S phase and the process could stimulate the expression of PCNA, Cyclin A and Cyclin E. In addition, we found that the p53 pathway was involved in MEG3–induced smooth muscle cell proliferation. Conclusions: This study identified MEG3 as a critical regulator in PAH and demonstrated the potential of gene therapy and drug development for treating PAH.

A natural product phillygenin suppresses osteosarcoma growth and metastasis by regulating the SHP-1/JAK2/STAT3 signaling

2021 ◽  
Vol 85 (2) ◽  
pp. 307-314
Author(s):  
Xiaomin Ding ◽  
Danqing Lu ◽  
Jianbo Fan
Keyword(s):  
Cell Growth ◽  
Signaling Pathway ◽  
Janus Kinase ◽  
Potential Candidate ◽  
Osteosarcoma Cell ◽  
Cancer Cell Growth ◽  
Functional Roles ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

ABSTRACT Osteosarcoma represents one of the most devastating cancers due to its high metastatic potency and fatality. Osteosarcoma is insensitive to traditional chemotherapy. Identification of a small molecule that blocks osteosarcoma progression has been a challenge in drug development. Phillygenin, a plant-derived tetrahydrofurofuran lignin, has shown to suppress cancer cell growth and inflammatory response. However, how phillygenin plays functional roles in osteosarcoma has remained unveiled. In this study, we showed that phillygenin inhibited osteosarcoma cell growth and motility in vitro. Further mechanistic studies indicated that phillygenin blocked STAT3 signaling pathway. Phillygenin led to significant downregulation of Janus kinase 2 and upregulation of Src homology region 2 domain-containing phosphatase 1. Gene products of STAT3 regulating cell survival and invasion were also inhibited by phillygenin. Therefore, our studies provided the first evidence that phillygenin repressed osteosarcoma progression by interfering STAT3 signaling pathway. Phillygenin is a potential candidate in osteosarcoma therapy.

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