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 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.

Inflammation influences vascular remodeling through AT2 receptor expression and signaling

2000 ◽  
Vol 2 (1) ◽  
pp. 13-20 ◽  
Author(s):  
MASAHIRO AKISHITA ◽  
MASATSUGU HORIUCHI ◽  
HIROYUKI YAMADA ◽  
LUNAN ZHANG ◽  
GOTARO SHIRAKAMI ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Muscle Growth ◽  
Vascular Diseases ◽  
Lesion Size ◽  
Receptor Expression ◽  
Growth Inhibitory ◽  
Interferon Regulatory Factor 1

Akishita, Masahiro, Masatsugu Horiuchi, Hiroyuki Yamada, Lunan Zhang, Gotaro Shirakami, Kouichi Tamura, Yasuyoshi Ouchi, and Victor J. Dzau. Inflammation influences vascular remodeling through AT2 receptor expression and signaling. Physiol. Genomics 2: 13–20, 2000.—The AT2 receptor, which exerts growth inhibitory effects in cell culture, is present scantily in the adult vasculature but is reexpressed after vascular injury. To examine the in vivo role of this receptor in vascular diseases, we developed a mouse model of vascular remodeling and compared the responses in wild-type ( Agtr2+) and AT2 receptor knockout ( Agtr2−) mice. Polyethylene cuff placement on the femoral artery led to the vascular expression of cytokines, the transcriptional factor interferon regulatory factor-1 (IRF-1), and both the AT1 and AT2 receptors. Although the expressions of IRF-1 and AT1 receptor were induced to comparable levels in both the Agtr2+ and Agtr2− mice, the neointimal lesion size and the smooth muscle cell proliferation were twice greater in the Agtr2− than in the Agtr2+ mouse. Correlated with this difference, AT2 receptor expression was induced predominantly in the smooth muscle cells of Agtr2+ mouse. These results demonstrate that the AT2 receptor plays an important role in nonocclusive inflammatory injury by mediating the effects of inflammation on vascular smooth muscle growth inhibition.

scholarly journals Procontractile G protein–mediated signaling pathways antagonistically regulate smooth muscle differentiation in vascular remodeling

2012 ◽  
Vol 209 (12) ◽  
pp. 2277-2290 ◽  
Author(s):  
Till F. Althoff ◽  
Julián Albarrán Juárez ◽  
Kerstin Troidl ◽  
Cong Tang ◽  
Shengpeng Wang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Signaling Pathways ◽  
G Protein ◽  
Vascular Remodeling ◽  
Serum Response Factor ◽  
Vascular Diseases ◽  
Marker Genes ◽  
Differentiation Marker ◽  
Differentiation And Proliferation

Vascular smooth muscle (Sm) cells (VSMCs) are highly plastic. Their differentiation state can be regulated by serum response factor (SRF), which activates genes involved in Sm differentiation and proliferation by recruiting cofactors, such as members of the myocardin family and ternary complex factors (TCFs), respectively. However, the extracellular cues and upstream signaling mechanisms regulating SRF-dependent VSMC differentiation under in vivo conditions are poorly understood. In this study, we show that the procontractile signaling pathways mediated by the G proteins G12/G13 and Gq/G11 antagonistically regulate VSMC plasticity in different models of vascular remodeling. In mice lacking Gα12/Gα13 or their effector, the RhoGEF protein LARG, RhoA-dependent SRF-regulation was blocked and down-regulation of VSMC differentiation marker genes was enhanced. This was accompanied by an excessive vascular remodeling and exacerbation of atherosclerosis. In contrast, Sm-specific Gαq/Gα11 deficiency blocked activation of extracellular signal-regulated kinase 1/2 and the TCF Elk-1, resulting in a reduced VSMC dedifferentiation in response to flow cessation or vascular injury. These data show that the balanced activity of both G protein–mediated pathways in VSMCs is required for an appropriate vessel remodeling response in vascular diseases and suggest new approaches to modulate Sm differentiation in vascular pathologies.

261Decisive role of microRNA-494 in smooth muscle cell proliferation and vascular remodeling

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
K Knoepp ◽  
J Dutzmann ◽  
K Kalies ◽  
M Rieckmann ◽  
J M Daniel ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factors ◽  
Coronary Artery ◽  
Femoral Artery ◽  
Vascular Remodeling ◽  
Neointima Formation ◽  
Human Coronary Artery ◽  
Vascular Proliferative Diseases

Abstract Background Proliferation of vascular smooth muscle cells triggered by cytokines and growth factors is a main driver in the development of vascular proliferative diseases such as atherosclerosis and in-stent-restenosis after angioplasty. MicroRNAs (miR) are small noncoding RNAs that can inhibit the expression of multiple genes simultaneously. However, the contribution of microRNAs to the differential gene regulation that triggers vascular remodeling processes is not well understood. Methods and results Neointima formation was induced by a wire-mediated injury of the femoral artery in C57BL/6 mice. Microarray analysis of the developing neointimal lesion showed a strong reduction of miR-494 (0.411±0.04; p<0.05) at 7 days after injury. In order to investigate the expression levels of miRs in vascular cells, human coronary artery smooth muscle cells (SMC), human coronary artery endothelial cells and human monocytes were analyzed via microarray analysis. Intriguingly, miR-494 was found to be predominantly expressed in SMC via microarray and qPCR analysis. The regulation of miR-494 expression was further analyzed after stimulation of SMC with 10%FCS. Following this mitogenic stimulation, mir-494 expression dropped robustly and significantly in a time-dependent manner at 6, 9, and 24 hours. To investigate the functional impact of miR-494 on SMC proliferation, miR-494 was overexpressed using miR-494-mimics (20μM). Overexpression of miR-494 significantly reduced the FCS-induced proliferation of SMC as assessed by BrdU-incorporation. In silico analyses of potential target genes for miR-494 identified ROCK1 and Survivin, both important molecules in the mitogenic response of SMC to cytokines and growth factors, as potential targets of miR-494. Indeed, ROCK1 and Survivin were found down-regulated on the mRNA and protein level after transfection of SMC with miR-494 mimics and both mulecules could be identified as direct targets using luciferase reporter assays. Following the specific inhibition of miR-494 by local application (in a perivascular thermos-responsive, self-degrading pluronic gel) of an in vivo stabilized Pre-miR-494 after wire-induced injury of the mouse femoral artery, SMC proliferation was significantly reduced, as assessed by Ki67 immunofluorescence (26.3% vs 11.2%; p<0.05). Consistently, local application of Pre-miR-494 significantly reduced neointima formation (neointima/media ratio 2.31 in control vs 1.01 in treated animals; p<0.01). Conclusion Our results show that mir-494 is strongly down-regulated in proliferating SMC in vitro as well as during neointimal lesion formation in vivo. Moreover, overexpression/ reconstitution of miR-494 levels effectively prevented SMC proliferation and neointima formation, indicating an important functional role of miR-494 in these processes. Hence, miR-494 may represent an attractive SMC-specific target for future therapeutic interventions for the treatment of vascular proliferative diseases.

Abstract 424: Vascular Smooth Muscle Cell Expression of S100a12 in Vivo Induces Enhanced Oxidative Stress & Vascular Remodeling

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Marion Hofmann Bowman ◽  
Jeannine Wilk ◽  
Gene Kim ◽  
Yanmin Zhang ◽  
Jalees Rehman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Oxidative Dna Damage ◽  
Fold Increase ◽  
Brdu Incorporation ◽  
Elastic Fibers ◽  
Nuclear Staining

S100A12 is a small calcium binding protein that is a signal transduction ligand of the receptor for advance glycation endproducts (RAGE). S100A12, like RAGE, is expressed in the vessel wall of atherosclerotic vasculature, particularly in smooth muscle cells (SMC). While RAGE has been extensively implicated in inflammatory states such as atherosclerosis, the role of S100A12 is less clear. We tested the hypothesis that expression of human S100A12 directly exacerbates vascular inflammation. Several lines of Bl6/J transgenic mice (tg) expressing human S100A12 in SMC under control of the SM22a promoter were generated. Primary aortic SMC from tg and wild type (wt) littermates were isolated and analyzed for (i) proliferation using MTS/Formazan Assay and BrdU incorporation, (ii) oxidative stress using using flow cytometry with MitoSOX antibody, oxidative DNA damage using immunofluorescence microscopy with anti-8-oxo-dG antibody, and NF-kB activation measured by EMSA and (iii) cytokine expression measured by IL-6 ELISA. Furthermore, the aortas from tg and wt mice were examined. Results: Tg but not wt SMC expressed S100A12 protein. Tg SMC had a significant 1.9 to 2.7 fold increase in conversion of MTS into Formazan at 24–96 hours likely reflective of increased metabolic activity since BrdU incorporation into DNA was less in tg compared to wt SMC (4% vs 21% positive BrdU nuclei, p <0.05). Tg SMC showed significantly higher levels of mitochondrial generated ROS, nuclear staining for oxidative DNA damage which was not detected in the nuclei of wt SMC’s, and a 2.5 fold increase in NFkB activity. IL-6 production at baseline was higher in tg SMC’s (615 vs 213 pg/ml, p< 0.05) and increased dramatically after LPS treatment (10 ng/ml) in tg SMC’s (2130 vs 415 pg/ml). Histologic examination of the thoracic aorta at 10 weeks of age revealed increased collagen deposition in the aortic media with fragmentation and disarray of elastic fibers. In vivo ultrasound revealed a progressive dilation of the aortic arch from age 10 weeks to 16 weeks of age (1.27 to 1.60 mm, p<0.05) in tg but not in wt littermate mice (1.30 to 1.33 mm, p=0.1). These data reveal the novel finding that targeted expression of human S100A12 in SMC modulates oxidative stress, inflammation and vascular remodeling.

Abstract 512: Collagen Homologous Sequence R1R2 Mediates Vascular Remodeling by Decreasing Inflammation and Smooth Muscle Proliferation

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Ting-Hein Lee ◽  
Hou-Yu Chiang
Keyword(s):  
Smooth Muscle ◽  
Vascular Disease ◽  
Vascular Remodeling ◽  
Vessel Wall ◽  
Inflammatory Cell ◽  
Vascular Diseases ◽  
Inflammatory Cell Infiltration ◽  
Collagen I ◽  
Cell Infiltration ◽  
Ecm Proteins

The extracellular matrix (ECM) is a major constituent of the vessel wall. Except for providing a structural scaffold for cells, ECM controls numerous cellular functions like adhesion, growth, migration and differentiation. The components of ECM are mediated by the interplay between ECM synthesis, deposition, degradation and the interaction between ECM proteins. Vascular remodeling occurs in the vascular diseases and is characterized by endothelial cell activation, inflammatory cell infiltration, smooth muscle cell (SMC) proliferation/migration, and augmented deposition of ECM proteins. Collagen I is the major ECM component in the arterial wall, excess collagen I accumulation may exacerbate the vascular disease by further facilitating SMC proliferation/migration. Therefore, treatments to inhibit excess collagen deposition could provide a remedy for vascular disease. R1R2, a peptide derived from the bacterial adhesin SFS with sequence homology to collagen, is known to inhibit collagen I deposition by inhibiting the binding of fibronectin to collagen. Studies have revealed that R1R2 affects collagen I-dependent cell growth and migration in vitro. However, the in vivo functions of R1R2 during vascular remodeling remain unknown. We hypothesized that R1R2 prevents excess collagen I accumulation and SMC proliferation, resulting in decreased neointimal formation. We induced vascular remodeling by ligating the carotid artery on mice. Delivery of R1R2 was periadventially applied using pluronic gel and evaluated its effects on vascular remodeling, ECM deposition, SMC proliferation and differentiation. Morphometric analysis demonstrated that R1R2 reduced intima-media thickening by 50% compared to the control group. R1R2 treatment also decreased collagen I deposition in the vessel wall and maintained SMC in the contractile phenotype. Interestingly, R1R2 dramatically reduced inflammatory cell infiltration into the vessel by 80% accompanied with decreased VCAM-1 and ICAM-1. In conclusion, our data showed that R1R2 attenuates the vascular remodeling response by decreasing inflammation and SMC proliferation/migration. These studies provide a therapeutic potential of periadventitially delivering R1R2 in treating vascular diseases.

scholarly journals LncRNA-SMILR modulates RhoA/ROCK signaling by targeting miR-141 to regulate vascular remodeling in pulmonary arterial hypertension

2020 ◽  
Vol 319 (2) ◽  
pp. H377-H391 ◽  
Author(s):  
Si Lei ◽  
Fei Peng ◽  
Mei-Lei Li ◽  
Wen-Bing Duan ◽  
Cai-Qin Peng ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Long Noncoding Rna ◽  
Vascular Remodeling ◽  
Noncoding Rna ◽  
In Vivo Models ◽  
Pulmonary Arterial

Smooth muscle-enriched long noncoding RNA (SMILR), as a long noncoding RNA (lncRNA), was increased in pulmonary arterial hypertension (PAH) patients and in vitro and in vivo models. SMILR activated RhoA/ROCK signaling by targeting miR-141 to disinhibit its downstream target RhoA. SMILR knockdown or miR-141 overexpression inhibited hypoxia-induced cell proliferation and migration via repressing RhoA/ROCK signaling in pulmonary arterial smooth muscle cells (PASMCs), which was confirmed in vivo experiments that knockdown of SMILR inhibited vascular remodeling and alleviated PAH in rats. SMILR may be a promising and novel therapeutic target for the treatment and drug development of PAH.

scholarly journals Cytoplasmic p21Cip1/WAF1 regulates neurite remodeling by inhibiting Rho-kinase activity

2002 ◽  
Vol 158 (2) ◽  
pp. 321-329 ◽  
Author(s):  
Hiroyuki Tanaka ◽  
Toshihide Yamashita ◽  
Minoru Asada ◽  
Shuki Mizutani ◽  
Hideki Yoshikawa ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Developmental Process ◽  
Ectopic Expression ◽  
Rho Kinase ◽  
Nuclear Antigen ◽  
Nih3t3 Cells ◽  
Localization Signal ◽  
Newborn Neurons

p21Cip1/WAF1 has cell cycle inhibitory activity by binding to and inhibiting both cyclin/Cdk kinases and proliferating cell nuclear antigen. Here we show that p21Cip1/WAF1 is induced in the cytoplasm during the course of differentiation of chick retinal precursor cells and N1E-115 cells. Ectopic expression of p21Cip1/WAF1 lacking the nuclear localization signal in N1E-115 cells and NIH3T3 cells affects the formation of actin structures, characteristic of inactivation of Rho. p21Cip1/WAF1 forms a complex with Rho-kinase and inhibits its activity in vitro and in vivo. Neurite outgrowth and branching from the hippocampal neurons are promoted if p21Cip1/WAF1 is expressed abundantly in the cytoplasm. These results suggest that cytoplasmic p21Cip1/WAF1 may contribute to the developmental process of the newborn neurons that extend axons and dendrites into target regions.

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