共查询到20条相似文献,搜索用时 15 毫秒
1.
De-differentiation of vascular smooth muscle cells (VSMCs) plays a critical role in the development of atherosclerosis, a chronic inflammatory disease involving various cytokines such as tumor necrosis factor-α (TNFα). Myocardin is a co-factor of serum response factor (SRF) and is considered to be the master regulator of VSMC differentiation. It binds to SRF and regulates the expression of contractile proteins in VSMCs. Myocardin is also known to inhibit VSMC proliferation by inhibiting the NF-κB pathway, whereas TNFα is known to activate the NF-κB pathway in VSMCs. NF-κB activation has also been shown to inhibit myocardin expression and smooth muscle contractile marker genes. However, it is not definitively known whether TNFα regulates the expression and activity of myocardin in VSMCs. The current study aimed to investigate the role of TNFα in regulating myocardin and VSMC function. Our studies showed that TNFα down-regulated myocardin expression and activity in cultured VSMCs by activating the NF-κB pathway, resulting in decreased VSMC contractility and increased VSMC proliferation. Surprisingly, we also found that TNFα prevented myocardin mRNA degradation, and resulted in a further significant increase in myocardin expression and activity in differentiated VSMCs. Both the NF-κB and p44/42 MAPK pathways were involved in TNFα regulation of myocardin, which further increased the contractility of VSMCs. These differential effects of TNFα on myocardin seemingly depended on whether VSMCs were in a differentiated or de-differentiated state. Taken together, our results demonstrate that TNFα differentially regulates myocardin expression and activity, which may play a key role in regulating VSMC functions. 相似文献
2.
Maria Alicia Carrillo-Sepulveda Henry L. Keen Deborah R. Davis Justin L. Grobe Curt D. Sigmund 《PloS one》2014,9(8)
Peroxisome proliferator activated receptor γ (PPARγ) has been reported to play a protective role in the vasculature; however, the underlying mechanisms involved are not entirely known. We previously showed that vascular smooth muscle-specific overexpression of a dominant negative human PPARγ mutation in mice (S-P467L) leads to enhanced myogenic tone and increased angiotensin-II-dependent vasoconstriction. S-P467L mice also exhibit increased arterial blood pressure. Here we tested the hypotheses that a) mesenteric smooth muscle cells isolated from S-P467L mice exhibit enhanced angiotensin-II AT1 receptor signaling, and b) the increased arterial pressure of S-P467L mice is angiotensin-II AT1 receptor dependent. Phosphorylation of mitogen-activated protein/extracellular signal-regulated kinase (ERK1/2) was robustly increased in mesenteric artery smooth muscle cell cultures from S-P467L in response to angiotensin-II. The increase in ERK1/2 activation by angiotensin-II was blocked by losartan, a blocker of AT1 receptors. Angiotensin-II-induced ERK1/2 activation was also blocked by Tempol, a scavenger of reactive oxygen species, and correlated with increased Nox4 protein expression. To investigate whether endogenous renin-angiotensin system activity contributes to the elevated arterial pressure in S-P467L, non-transgenic and S-P467L mice were treated with the AT1 receptor blocker, losartan (30 mg/kg per day), for 14-days and arterial pressure was assessed by radiotelemetry. At baseline S-P467L mice showed a significant increase of systolic arterial pressure (142.0±10.2 vs 129.1±3.0 mmHg, p<0.05). Treatment with losartan lowered systolic arterial pressure in S-P467L (132.2±6.9 mmHg) to a level similar to untreated non-transgenic mice. Losartan also lowered arterial pressure in non-transgenic (113.0±3.9 mmHg) mice, such that there was no difference in the losartan-induced depressor response between groups (−13.53±1.39 in S-P467L vs −16.16±3.14 mmHg in non-transgenic). Our results suggest that interference with PPARγ in smooth muscle: a) causes enhanced angiotensin-II AT1 receptor-mediated ERK1/2 activation in resistance vessels, b) and may elevate arterial pressure through both angiotensin-II AT1 receptor-dependent and -independent mechanisms. 相似文献
3.
Eugénie Goupil Dany Fillion Stéphanie Clément Xiaoyan Luo Dominic Devost Rory Sleno Darlaine Pétrin H. Uri Saragovi éric Thorin Stéphane A. Laporte Terence E. Hébert 《The Journal of biological chemistry》2015,290(5):3137-3148
The angiotensin II type I (AT1R) and the prostaglandin F2α (PGF2α) F prostanoid (FP) receptors are both potent regulators of blood pressure. Physiological interplay between AT1R and FP has been described. Abdominal aortic ring contraction experiments revealed that PGF2α-dependent activation of FP potentiated angiotensin II-induced contraction, whereas FP antagonists had the opposite effect. Similarly, PGF2α-mediated vasoconstriction was symmetrically regulated by co-treatment with AT1R agonist and antagonist. The underlying canonical Gαq signaling via production of inositol phosphates mediated by each receptor was also regulated by antagonists for the other receptor. However, binding to their respective agonists, regulation of receptor-mediated MAPK activation and vascular smooth muscle cell growth were differentially or asymmetrically regulated depending on how each of the two receptors were occupied by either agonist or antagonist. Physical interactions between these receptors have never been reported, and here we show that AT1R and FP form heterodimeric complexes in both HEK 293 and vascular smooth muscle cells. These findings imply that formation of the AT1R/FP dimer creates a novel allosteric signaling unit that shows symmetrical and asymmetrical signaling behavior, depending on the outcome measured. AT1R/FP dimers may thus be important in the regulation of blood pressure. 相似文献
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Hao Zheng Qi Li Rui Chen Jing Zhang Yong Ran Xiao He Shu Li Hong-Bing Shu 《The Journal of biological chemistry》2013,288(2):819-825
6.
Aung Than Melvin Khee-Shing Leow Peng Chen 《The Journal of biological chemistry》2013,288(22):15520-15531
Angiotensin II (AngII), a peptide hormone released by adipocytes, can be catabolized by adipose angiotensin-converting enzyme 2 (ACE2) to form Ang(1–7). Co-expression of AngII receptors (AT1 and AT2) and Ang(1–7) receptors (Mas) in adipocytes implies the autocrine regulation of the local angiotensin system upon adipocyte functions, through yet unknown interactive mechanisms. In the present study, we reveal the adipogenic effects of Ang(1–7) through activation of Mas receptor and its subtle interplays with the antiadipogenic AngII-AT1 signaling pathways. Specifically, in human and 3T3-L1 preadipocytes, Ang(1–7)-Mas signaling promotes adipogenesis via activation of PI3K/Akt and inhibition of MAPK kinase/ERK pathways, and Ang(1–7)-Mas antagonizes the antiadipogenic effect of AngII-AT1 by inhibiting the AngII-AT1-triggered MAPK kinase/ERK pathway. The autocrine regulation of the AngII/AT1-ACE2-Ang(1–7)/Mas axis upon adipogenesis has also been revealed. This study suggests the importance of the local regulation of the delicately balanced angiotensin system upon adipogenesis and its potential as a novel therapeutic target for obesity and related metabolic disorders. 相似文献
7.
Sara Gorjestani Bryant G. Darnay Xin Lin 《The Journal of biological chemistry》2012,287(53):44143-44150
Tumor necrosis factor receptor-associated factor 6 (TRAF6) and TGFβ-activated kinase 1 (TAK1) are considered as key intermediates in Toll-like receptor (TLR) signaling. However, the role of TRAF6 and TAK1 in C-type lectin receptors (CLRs) in response to fungal infection has not been studied. In this study, we have utilized macrophages derived from TRAF6 knock-out mice and myeloid-specific TAK1-deficient mice and determined the role of TRAF6 and TAK1 in CLR-induced signal transduction events. We demonstrate that TRAF6 and TAK1 are required for NF-κB and JNK activation, and expression of proinflammatory cytokines in response to Candida albicans infection. Our results highlight TRAF6 and TAK1 as key components in the signaling cascade downstream of C-type lectin receptors and as critical mediators of the anti-fungal immune response. Therefore, our studies provide a mechanistic understanding of the host immune response to C. albicans, which has a significant impact for the development of anti-fungal therapeutics and in understanding risk-factors and determining susceptibility to C. albicans infection. 相似文献
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Hui-xuan Li Mei Han Michel Bernier Bin Zheng Shao-guang Sun Ming Su Rui Zhang Jian-ran Fu Jin-kun Wen 《The Journal of biological chemistry》2010,285(23):17846-17856
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Jihee Kim Seungkirl Ahn Keshava Rajagopal Robert J. Lefkowitz 《The Journal of biological chemistry》2009,284(18):11953-11962
Recent studies in receptor-transfected cell lines have demonstrated that
extracellular signal-regulated kinase (ERK) activation by angiotensin type 1A
receptor and other G protein-coupled receptors can be mediated by both G
protein-dependent and β-arrestin-dependent mechanisms. However, few
studies have explored these mechanisms in primary cultured cells expressing
endogenous levels of receptors. Accordingly, here we utilized the
β-arrestin biased agonist for the angiotensin type 1A receptor,
SII-angiotensin (SII), and RNA interference techniques to investigate
angiotensin II (ANG)-activated β-arrestin-mediated mitogenic signaling
pathways in rat vascular smooth muscle cells. Both ANG and SII induced DNA
synthesis via the ERK activation cascade. Even though SII cannot induce
calcium influx (G protein activation) after receptor stimulation, it does
cause ERK activation, although less robustly than ANG. Activation by both
ligands is diminished by depletion of β-arrestin2 by small interfering
RNA, although the effect is more complete with SII. ERK activation at early
time points but not later time points is strongly inhibited by those protein
kinase C inhibitors that can block protein kinase Cζ. Moreover, ANG- and
SII-mediated ERK activation require transactivation of the epidermal growth
factor receptor via metalloprotease 2/9 and Src kinase. β-Arrestin2
facilitates ANG and SII stimulation of Src-mediated phosphorylation of Tyr-845
on the EGFR, a known site for Src phosphorylation. These studies delineate a
convergent mechanism by which G protein-dependent and
β-arrestin-dependent pathways can independently mediate ERK-dependent
transactivation of the EGFR in vascular smooth muscle cells thus controlling
cellular proliferative responses.G protein-coupled receptors, also known as seven transmembrane
(7TM)2 receptors,
control virtually all known physiological processes in mammals
(1). The various functions of
these receptors are mediated and modulated by three families of proteins,
which share the property that they interact virtually universally with the
receptors in a strictly stimulus-dependent way
(1). These three families of
proteins are the heterotrimeric G proteins, the G protein-coupled receptor
kinases (GRKs), and the β-arrestins. Activation of the receptors
stimulates classical G protein-dependent signaling, often involving regulation
of levels of second messengers such as cAMP and diacyglycerol. However, as has
been known for many years, interaction of activated receptors with GRKs
leading to their phosphorylation, and subsequent interaction with
β-arrestins leads to desensitization of G protein signaling.In recent years, however, it has become increasingly clear that the
β-arrestin-GRK system is in fact bifunctional
(2). Thus, even as it
desensitizes G protein signaling by the receptors, it also serves as a signal
transduction system in its own right, activating a growing list of signaling
pathways. These positive signaling functions are often mediated by the ability
of β-arrestin to serve as an adaptor or scaffold molecule, bringing
elements of diverse signaling pathways into proximity with one another and the
receptors and thereby facilitating their activation. This new paradigm for
understanding the previously unrecognized signaling properties of the
β-arrestin-GRK system has been explored in a wide variety of transfected
cultured cell systems.However, to date, relatively little investigation of these novel signaling
pathways has been carried out in primary cell culture systems expressing
endogenous levels of 7TM receptors. In seeking such a system in which to
characterize and compare β-arrestin and G protein-mediated signaling
pathways from a typical 7TM receptor, our attention was drawn to cultured rat
vascular smooth muscle cells (VSMCs). Several features of rat VSMCs suggest
this to be a relevant system for these purposes. Rat VSMCs express a variety
of physiologically important 7TM receptors including the angiotensin II type
1A receptor (AT1R) (3). This
receptor has been the focus of extensive study in transfected cell systems
with respect to its β-arrestin-mediated signaling to a variety of
pathways, most particularly extracellular signal-regulated kinase (ERK).
Moreover, the AT1R mediates the physiologically important effects of
angiotensin II (ANG) on vascular tone as well as on proliferation and
chemotaxis (4,
5). Pathophysiologically, ANG
stimulation of this receptor has been implicated in VSMC proliferation and
chemotaxis, which are thought to play an important role in such important
disease processes as atherosclerosis and restenosis after angioplasty
(6,
7). Moreover, a ligand has been
characterized
[Sar1,Ile4,Ile8](SII)-angiotensin (SII), a
triply mutated angiotensin octapeptide that, in transfected cell systems, acts
as a specific agonist for β-arrestin-mediated signaling, although not
activating G protein-mediated signaling
(8).Accordingly, in the studies described here, we set out to investigate the
characteristics of activation of ERK in rat VSMCs that might be mediated
through G protein as well as β-arrestin signaling. The results not only
demonstrate the importance of β-arrestin-mediated signaling in
ERK-mediated proliferative responses of these cells, but also shed new light
on the molecular mechanisms and interrelationships between the β-arrestin
and classical G protein-mediated activation of these pathways. 相似文献
15.
Raffaella Scaringi Marco Piccoli Nadia Papini Federica Cirillo Erika Conforti Sonia Bergante Cristina Tringali Andrea Garatti Cecilia Gelfi Bruno Venerando Lorenzo Menicanti Guido Tettamanti Luigi Anastasia 《The Journal of biological chemistry》2013,288(5):3153-3162
NEU3 sialidase, a key enzyme in ganglioside metabolism, is activated under hypoxic conditions in cultured skeletal muscle cells (C2C12). NEU3 up-regulation stimulates the EGF receptor signaling pathway, which in turn activates the hypoxia-inducible factor (HIF-1α), resulting in a final increase of cell survival and proliferation. In the same cells, stable overexpression of sialidase NEU3 significantly enhances cell resistance to hypoxia, whereas stable silencing of the enzyme renders cells more susceptible to apoptosis. These data support the working hypothesis of a physiological role played by NEU3 sialidase in protecting cells from hypoxic stress and may suggest new directions in the development of therapeutic strategies against ischemic diseases, particularly of the cerebro-cardiovascular system. 相似文献
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Anika H?vemeier Silvia Gramolelli Marcel Pietrek Ramona Jochmann Michael Stürzl Thomas F. Schulz 《Journal of virology》2014,88(22):13161-13172
18.
Sònia Tugues Satoshi Honjo Christian K?nig Narendra Padhan Jeffrey Kroon Laura Gualandi Xiujuan Li Irmeli Barkefors Victor L. Thijssen Arjan W. Griffioen Lena Claesson-Welsh 《The Journal of biological chemistry》2013,288(26):19060-19071
CD63 is a member of the transmembrane-4 glycoprotein superfamily (tetraspanins) implicated in the regulation of membrane protein trafficking, leukocyte recruitment, and adhesion processes. We have investigated the involvement of CD63 in endothelial cell (EC) signaling downstream of β1 integrin and VEGF. We report that silencing of CD63 in primary ECs arrested capillary sprouting and tube formation in vitro because of impaired adhesion and migration of ECs. Mechanistically, CD63 associated with both β1 integrin and the main VEGF receptor on ECs, VEGFR2. Our data suggest that CD63 serves to bridge between β1 integrin and VEGFR2 because CD63 silencing disrupted VEGFR2-β1 integrin complex formation identified using proximity ligation assays. Signaling downstream of β1 integrin and VEGFR2 was attenuated in CD63-silenced cells, although their cell surface expression levels remained unaffected. CD63 was furthermore required for efficient internalization of VEGFR2 in response to VEGF. Importantly, systemic delivery of VEGF failed to potently induce VEGFR2 phosphorylation and downstream signaling in CD63-deficient mouse lungs. Taken together, our findings demonstrate a previously unrecognized role for CD63 in coordinated integrin and receptor tyrosine kinase signaling in vitro and in vivo. 相似文献
19.
Gao Cheng Liu Wei Wang Xiurong Liu Xiangzhen Zhao Shiguang Fu Songbin 《Cellular and molecular neurobiology》2009,29(8):1161-1168
Inappropriate vascular remodeling is thought to be the main cause of restenosis following angioplasty. Migration of vascular
smooth muscle cells (VSMC) into lumina, which is promoted by degradation of the extracellular matrix by matrix metalloproteinases
(MMPs) plays a causal role in pathological vascular remodeling. The aim of the present research is to explore the effects
of a novel cytokine, IL-17, on migration of VSMC and MMP-9 secretion. Carotid artery VSMC was isolated from Sprague–Dawley
rats. Expression of MMP-9 and cell migration induced by IL-17 and its related signal pathway were detected. The results showed
that IL-17-induced migration of VSMC in an MMP-9-dependent manner. IL-17-induced MMP-9 expression was via p38 MAPK and ERK1/2
dependent NF-κB and AP-1 activation. The present results demonstrated that IL-17 may play a role in vascular remodeling and
targeting IL-17 or its specific downstream mediators is a potentially novel therapeutic pathway for attenuating the post-angioplastic
restenosis. 相似文献
20.
Chih-Pei Lin Po-Hsun Huang Chung Fang Lai Jaw-Wen Chen Shing-Jong Lin Jia-Shiong Chen 《PloS one》2015,10(12)
Simvastatin (SIM) is anti-inflammatory. We used low density lipoprotein receptor knockout (LDLR-/-) mice and human aortic smooth muscle cells (HASMCs) as model systems to study the effect of SIM on arterial calcification and to explore the potential mechanisms contributing to this protective effect. High-fat diet (HFD) caused the LRLR -/- to develop dyslipidemia, diabetics, atherosclerosis and aortic smooth muscle calcification. SIM, N-acetyl cysteine (NAC, a ROS scavenger) and apocynin (APO, a NADPH oxidase inhibitor) did not significantly retard the development of dyslipidemia or diabetic. However, those treatments were still effective in attenuating the HFD-induced atherosclerosis and aortic smooth muscle calcification. These findings suggest that the protective effect of SIM against aortic calcification is not contributed by the cholesterol lowering effect. SIM, NAC and APO were found to attenuate the HFD induced elevation of serum TNF-α, soluble TNFR1 (sTNFR1), 3-nitro-tyrosine. We hypothesized that the pro-inflammatory cytokine, oxidative stress and TNFR1 played a role in inducing aortic calcification. We used HASMC to investigate the role of TNF-α, oxidative stress and TNFR1 in inducing aortic calcification and to elucidate the mechanism contributes the protective effect of SIM against aortic calcification. We demonstrated that treating HASMC with TNF-α induced cell Ca deposit and result in an increase in ALP, NADPH oxidase activity, NF-kB subunit p65, BMP2, MSX2, and RUNX2 expression. SIM suppressed the TNF-α induced activation of NADPH oxidase subunit p47, the above-mentioned bone markers and TNFR1 expression. Furthermore, p65, p47 and TNFR1 siRNAs inhibited the TNF-α-mediated stimulation of BMP-2, MSX2, RUNX2 expression. SIM, APO, and NAC either partially inhibit or completely block the TNF-α induced H2O2 or superoxide production. These results suggest that SIM may, independent of its cholesterol-lowering effect, suppresses the progression of vascular diseases through the inhibition of the inflammation mediators TNF-α and TNFR1. 相似文献