共查询到20条相似文献,搜索用时 46 毫秒
1.
Yamaji-Kegan K Su Q Angelini DJ Champion HC Johns RA 《American journal of physiology. Lung cellular and molecular physiology》2006,291(6):L1159-L1168
From a mouse model of hypoxia-induced pulmonary hypertension, we previously found a highly upregulated protein in the lung that we named hypoxia-induced mitogenic factor (HIMF), also known as found in inflammatory zone 1 (FIZZ1), and resistin-like molecule alpha (RELMalpha). However, the mechanisms of HIMF in the pulmonary vascular remodeling remain unknown. We now demonstrate that HIMF promoted cell proliferation, migration, and the production of vascular endothelial growth factor (VEGF) and monocyte chemotactic protein-1 (MCP-1) in pulmonary endothelial cells as well as the production of reactive oxygen species in murine monocyte/macrophage cells. HIMF-induced CD31-positive cell infiltrate in in vivo Matrigel plugs was significantly suppressed by VEGF receptor-2 (VEGFR2) blockade. In ex vivo studies, HIMF stimulated the production of VEGF, MCP-1, and stromal cell-derived factor-1 (SDF-1) in the lung resident cells, and VEGFR2 neutralization significantly suppressed HIMF-induced MCP-1 and SDF-1 production. Furthermore, intravenous injection of HIMF showed marked increase of CD68-positive inflammatory cells in the lungs, and these events were attenuated by VEGFR2 neutralization. Intravenous injection of HIMF also downregulated the expression of VEGFR2 in the lung. These results suggest that HIMF plays critical roles in pulmonary inflammation as well as angiogenesis. 相似文献
2.
Crosstalk between the cyclic AMP-dependent protein kinase (PKA) and growth factor receptor signaling is one of many emerging concepts of crosstalk in signal transduction. Understanding of PKA crosstalk may have important implications for studies of crosstalk between other, less well known, signaling pathways. This review focuses on PKA crosstalk in arterial smooth muscle. Proliferation and migration of arterial smooth muscle cells (SMCs) contribute to the thickening of the blood vessel wall that occurs in many types of cardiovascular disease. PKA potently inhibits SMC proliferation by antagonizing the major mitogenic signaling pathways induced by growth factors in SMCs. PKA also inhibits growth factor-induced SMC migration. An intricate crosstalk between PKA and the mitogen-activated protein kinase (MAPK/ERK) pathway, the p70 S6 kinase pathway and cyclin-dependent kinases has been described. Further, PKA regulates expression of growth regulatory molecules. The result of PKA activation in SMCs is the potent inhibition of cell cycle traverse and SMC migration. In this review, we discuss recent advances in our understanding of the crosstalk between PKA and signaling pathways induced by growth factor receptors in SMCs, and where relevant, in other cell types in which interesting examples of PKA crosstalk have been described. 相似文献
3.
Yamaji-Kegan K Su Q Angelini DJ Myers AC Cheadle C Johns RA 《Journal of immunology (Baltimore, Md. : 1950)》2010,185(9):5539-5548
4.
Tong Q Zheng L Li B Wang D Huang C Matuschak GM Li D 《Experimental cell research》2006,312(18):3559-3569
Our previous studies have indicated that hypoxia-induced mitogenic factor (HIMF) has angiogenic properties in an in vivo matrigel plug model and HIMF upregulates expression of vascular endothelial growth factor (VEGF) in mouse lungs and cultured lung epithelial cells. However, whether HIMF exerts angiogenic effects through modulating endothelial cell function remains unknown. In this study, mouse aortic rings cultured with recombinant HIMF protein resulted in enhanced vascular sprouting and increased endothelial cell spreading as confirmed by Dil-Ac-LDL uptake, von Willebrand factor and CD31 staining. In cultured mouse endothelial cell line SVEC 4-10, HIMF dose-dependently enhanced cell proliferation, in vitro migration and tubulogenesis, which was not attenuated by SU1498, a VEGFR2/Flk-1 receptor tyrosine kinase inhibitor. Moreover, HIMF stimulation resulted in phosphorylation of Akt, p38 and ERK1/2 kinases in SVEC 4-10 cells. Treatment of mouse aortic rings and SVEC 4-10 cells with LY294002, but not SB203580, PD098059 or U0126, abolished HIMF-induced vascular sprouting and angiogenic responses. In addition, transfection of a dominant-negative mutant of phosphatidylinositol 3-kinase (PI-3K), Deltap85, blocked HIMF-induced phosphorylation of Akt, endothelial activation and tubulogenesis. These results indicate that HIMF enhances angiogenesis by promoting proliferation and migration of endothelial cells via activation of the PI-3K/Akt pathways. 相似文献
5.
Preston IR Hill NS Warburton RR Fanburg BL 《American journal of physiology. Lung cellular and molecular physiology》2006,290(2):L367-L374
The 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism stimulates cell growth and metastasis of various cancer cells and the 12-LO metabolite, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], enhances proliferation of aortic smooth muscle cells (SMCs). However, pulmonary vascular effects of 12-LO have not been previously studied. We sought evidence for a role of 12-LO and 12(S)-HETE in the development of hypoxia-induced pulmonary hypertension. We found that 12-LO gene and protein expression is elevated in lung homogenates of rats exposed to chronic hypoxia. Immunohistochemical staining with a 12-LO antibody revealed intense staining in endothelial cells of large pulmonary arteries, SMCs (and possibly endothelial cells) of medium and small-size pulmonary arteries and in alveolar walls of hypoxic lungs. 12-LO protein expression was increased in hypoxic cultured rat pulmonary artery SMCs. 12(S)-HETE at concentrations as low as 10(-5) microM stimulated proliferation of pulmonary artery SMCs. 12(S)-HETE induced ERK 1/ERK 2 phosphorylation but had no effect on p38 kinase expression as assessed by Western blotting. 12(S)-HETE-stimulated SMC proliferation was blocked by the MEK inhibitor PD-98059, but not by the p38 MAPK inhibitor SB-202190. Hypoxia (3%)-stimulated pulmonary artery SMC proliferation was blocked by both U0126, a MEK inhibitor, and baicalein, an inhibitor of 12-LO. We conclude that 12-LO and its product, 12(S)-HETE, are important intermediates in hypoxia-induced pulmonary artery SMC proliferation and may participate in hypoxia-induced pulmonary hypertension. 相似文献
6.
Zhouguang Wang Liping Jiang Ran Chen Xiaofang Fan Huanmian Zhu Liping Han Xiaokun Li Jian Xiao Xiaoxia Kong 《Journal of cellular and molecular medicine》2014,18(3):542-553
Apelin is highly expressed in the lungs, especially in the pulmonary vasculature, but the functional role of apelin under pathological conditions is still undefined. Hypoxic pulmonary hypertension is the most common cause of acute right heart failure, which may involve the remodeling of artery and regulation of autophagy. In this study, we determined whether treatment with apelin regulated the proliferation and migration of rat pulmonary arterial smooth muscle cells (SMCs) under hypoxia, and investigated the underlying mechanism and the relationship with autophagy. Our data showed that hypoxia activated autophagy significantly at 24 hrs. The addition of exogenous apelin decreased the level of autophagy and further inhibited pulmonary arterial SMC (PASMC) proliferation via activating downstream phosphatidylinositol‐3‐kinase (PI3K)/protein kinase B (Akt)/the mammalian target of Rapamycin (mTOR) signal pathways. The inhibition of the apelin receptor (APJ) system by siRNA abolished the inhibitory effect of apelin in PASMCs under hypoxia. This study provides the evidence that exogenous apelin treatment contributes to inhibit the proliferation and migration of PASMCs by regulating the level of autophagy. 相似文献
7.
Renigunta A Hild C Rose F Klepetko W Grimminger F Seeger W Hänze J 《FEBS letters》2006,580(3):900-903
RELMbeta (resistin-like molecule) represents the most related human homologue of mouse RELMalpha, also known as hypoxic-induced mitogenic factor (HIMF). In this study, we isolated RELMbeta cDNA from human lung tissue and performed regulatory and functional expression studies. RELMbeta mRNA was upregulated in hypoxia in human lung A549 cell line as well as primary cultured adventitial fibroblasts and smooth muscle cells (SMC) of pulmonary arteries. Upon transfection of a RELMbeta encoding expression plasmid into these cells, we observed significant induction of proliferation particularly in SMC and A549 cells, which could be blocked by phosphatidyl-inositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin. The results suggest that human RELMbeta may contribute to hypoxic-induced pulmonary vascular remodeling processes or hypoxia related fibrotic lung disease. 相似文献
8.
The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration 总被引:28,自引:0,他引:28
Streblow DN Soderberg-Naucler C Vieira J Smith P Wakabayashi E Ruchti F Mattison K Altschuler Y Nelson JA 《Cell》1999,99(5):511-520
Human cytomegalovirus (HCMV) infection of smooth muscle cells (SMCs) in vivo has been linked to a viral etiology of vascular disease. In this report, we demonstrate that HCMV infection of primary arterial SMCs results in significant cellular migration. Ablation of the chemokine receptor, US28, abrogates SMC migration, which is rescued only by expression of the viral homolog and not a cellular G protein-coupled receptor (GPCR). Expression of US28 in the presence of CC chemokines including RANTES or MCP-1 was sufficient to promote SMC migration by both chemokinesis and chemotaxis, which was inhibited by protein tyrosine kinase inhibitors. US28-mediated SMC migration provides a molecular basis for the correlative evidence that links HCMV to the acceleration of vascular disease. 相似文献
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The synthetic peptide, SFLLRNPNDKYEPF, has been recently described as a peptide mimicking the new amino-terminus created by cleavage of the thrombin receptor, therefore acting as an agonist of the thrombin receptor. This peptide was a potent mitogen for rabbit arterial smooth muscle cells (SMC) and exhibited the same activity as that of native alpha-thrombin. Both compounds stimulated the proliferation of growth-arrested SMCs with half-maximum mitogenic responses at 1 nM. NAPAP, a synthetic inhibitor of the enzymatic activity of thrombin, specifically inhibited thrombin-induced SMC growth (IC50 = 0.35 +/- 0.04 microM) but was without effect on the mitogenic effect of the agonist peptide. These results therefore demonstrate that the mitogenic effect of alpha-thrombin for SMCs is intimately linked to its esterolytic activity. Heparin, which inhibited fetal calf serum-induced SMC growth, was without effect on thrombin-induced SMC growth but strongly reduced the mitogenic effect of the agonist peptide (IC50 = 32 +/- 5 micrograms/ml). This effect was not related to the anti-coagulant activity of heparin but was highly dependent on molecular mass and on the global charge of the molecule and was also observed for other sulphated polysaccharides such as pentosan polysulphate. 相似文献
12.
ERK,JNK, and p38 MAP kinases differentially regulate proliferation and migration of phenotypically distinct smooth muscle cell subtypes 总被引:12,自引:0,他引:12
Proliferation and migration of vascular smooth muscle cells (SMCs) are important processes involved in the pathogenesis of vascular disorders such as atherosclerosis and post-angioplasty restenosis. Here we demonstrate that proliferation and migration of specific SMC subtypes is mitogen-activated protein (MAP) kinase-dependent. WKY12-22 SMCs derived from the aortae of 12 day-old pup rats proliferate and migrate faster than WKY3M-22 SMCs derived from the aortae of adult rats. WKY12-22 and WKY3M-22 cells equally expressed the active forms of phospho (Thr(183)/Tyr(185))-c-Jun N-terminal kinase (JNK) and phospho (Tyr(182))-p38, whereas the activity of extracellular signal-regulated kinase (ERK) was greater in WKY12-22 cells compared with WKY3M-22 cells. Proliferation of both SMC subtypes was attenuated by PD98059, SP600125 and SB202190, inhibitors of ERK, JNK, and p38, respectively. However, inhibition of PD98059 had a more profound effect on WKY12-22 SMCs. Furthermore, migration of WKY12-22 and WKY3M-22 cells was inhibited by SP600125 and SB202190, however, PD98059 failed to influence migration of either SMC subtype. Hence, migration of both SMC subtypes is JNK- and p38-dependent, but not ERK-dependent. These findings demonstrate that SMC heterogeneity is mediated, at least in part, by the activity of specific MAP kinase subtypes. 相似文献
13.
Platelet-derived growth factor BB induces nuclear export and proteasomal degradation of CREB via phosphatidylinositol 3-kinase/Akt signaling in pulmonary artery smooth muscle cells
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Garat CV Fankell D Erickson PF Reusch JE Bauer NN McMurtry IF Klemm DJ 《Molecular and cellular biology》2006,26(13):4934-4948
Cyclic AMP response element binding protein (CREB) content is diminished in smooth muscle cells (SMCs) in remodeled pulmonary arteries from animals with pulmonary hypertension and in the SMC layers of atherogenic systemic arteries and cardiomyocytes from hypertensive individuals. Loss of CREB can be induced in cultured SMCs by chronic exposure to hypoxia or platelet-derived growth factor BB (PDGF-BB). Here we investigated the signaling pathways and mechanisms by which PDGF elicits depletion of SMC CREB. Chronic PDGF treatment increased CREB ubiquitination in SMCs, while treatment of SMCs with the proteasome inhibitor lactacystin prevented decreases in CREB content. The nuclear export inhibitor leptomycin B also prevented depletion of SMC CREB alone or in combination with lactacystin. Subsequent studies showed that PDGF activated extracellular signal-regulated kinase, Jun N-terminal protein kinase, and phosphatidylinositol 3 (PI3)-kinase pathways in SMCs. Inhibition of these pathways blocked SMC proliferation in response to PDGF, but only inhibition of PI3-kinase or its effector, Akt, blocked PDGF-induced CREB loss. Finally, chimeric proteins containing enhanced cyan fluorescent protein linked to wild-type CREB or CREB molecules with mutations in several recognized phosphorylation sites were introduced into SMCs. PDGF treatment reduced the levels of each of these chimeric proteins except for one containing mutations in adjacent serine residues (serines 103 and 107), suggesting that CREB loss was dependent on CREB phosphorylation at these sites. We conclude that PDGF stimulates nuclear export and proteasomal degradation of CREB in SMCs via PI3-kinase/Akt signaling. These results indicate that in addition to direct phosphorylation, proteolysis and intracellular localization are key mechanisms regulating CREB content and activity in SMCs. 相似文献
14.
CeReS-18, a cell regulatory sialoglycopeptide, has been shown to inhibit proliferation of a wide array of target cells. In the present study, the effect of CeReS-18 on vascular smooth muscle cell (SMC) proliferation was characterized in cultured rat aorta SMCs (A7r5). More extensively, the effect of CeReS-18 on platelet-derived growth factor (PDGF)-induced SMC migration was examined using a modified Boyden's chamber assay. CeReS-18 inhibits both SMC proliferation and migration in a concentration-dependent, calcium-sensitive, and reversible manner. Furthermore, cells preincubated with the inhibitor had an increased sensitivity to CeReS-18-mediated inhibition of SMC migration. Immunoprecipitation and in vitro phosphorylation assays demonstrated that MAP kinase activity was inhibited in the CeReS-18-treated cells and pretreatment with CeReS-18 suppressed the activation of MAP kinase stimulated by PDGF. However, it is not likely that the suppression of the MAP kinase pathway was directly responsible for the ability of CeReS-18 to inhibit migration of the rat aorta smooth muscle cells since a MEK-specific inhibitor, PD98059, did not influence A7r5 cell migration. 相似文献
15.
S T Wong L P Baker K Trinh M Hetman L A Suzuki D R Storm K E Bornfeldt 《The Journal of biological chemistry》2001,276(36):34206-34212
Arterial smooth muscle cell (SMC) proliferation contributes to a number of vascular pathologies. Prostaglandin E(2) (PGE(2)), produced by the endothelium and by SMCs themselves, acts as a potent SMC growth inhibitor. The growth-inhibitory effects of PGE(2) are mediated through activation of G-protein-coupled membrane receptors, activation of adenylyl cyclases (ACs), formation of cAMP, and subsequent inhibition of mitogenic signal transduction pathways in SMCs. Of the 10 different mammalian AC isoforms known today, seven isoforms (AC2-7 and AC9) are expressed in SMCs from various species. We show that, despite the presence of several different AC isoforms, the principal AC isoform activated by PGE(2) in human arterial SMCs is a calmodulin kinase II-inhibited AC with characteristics similar to those of AC3. AC3 is expressed in isolated human arterial SMCs and in intact aorta. We further show that arterial SMCs isolated from AC3-deficient mice are resistant to PGE(2)-induced growth inhibition. In summary, AC3 is the principal AC isoform activated by PGE(2) in arterial SMCs, and AC3 mediates the growth-inhibitory effects of PGE(2). Because AC3 activity is inhibited by intracellular calcium through calmodulin kinase II, AC3 may serve as an important integrator of growth-inhibitory signals that stimulate cAMP formation and growth factors that increase intracellular calcium. 相似文献
16.
The present study analyzes smooth muscle myosin heavy chain (SMMHC) expression as lung microvascular precursor smooth muscle
cells (PSMCs), cells derived from fibroblasts and intermediate cells (immature SMCs), acquire a smooth muscle phenotype in
anin vivo model of pulmonary hypertension (PH). Because of the unique contractile properties of the SMMHC isoform SM-B, we
analyzed its expression in the microvessels (<100 μm diameter) and in larger vessels (100–700 μm) quantitatualy by the labeled
[strept]avidin-biotin technique (day 1–28), and related this to cell phenotype by transmission microscopy and protein A-gold
labeling (at day 28). Airway SMCs of the normal and hypertensive lung uniformly expressed SM-B whereas vascular SMC expression
was heterogeneous. Thus, in some large arteries (and veins) SMCs contained cells expressing SM-B while in others all the cells
were immunonegative. Microvascular cells expressing SM-B (arteries and veins) were rare in normal lung and numerous in PH,
increasing as wall muscle developed in smaller segments with time. As in large vessels, some microvessels had immunopositive
cells and others only negative ones. Ultrastructural analysis confirmed that the SMCs of bronchial vessels, and the septal
SMCs adjoining alveolar ducts, contained dense filament arrays decorated with SM-B. While the PSMC processes of the normal
lung contained sparse filaments decorated with SM-B, these cells expressed dense filament arrays in PH. Fibroblasts migrating
to align around the microvessels also expressed SM-B but in the absence of a filament network. For the first time,we demonstrate
in vivo that newly developed microvascular PSMCs express the SMMHC SM-B isoform in PH.
Received: 9 April 1998 / Accepted: 9 September 1998 相似文献
17.
D. A. Kostina I. V. Voronkina L. V. Smagina N. D. Gavriliuk O. M. Moiseeva O. B. Irtiuga V. E. Uspensky A. A. Kostareva A. B. Malashicheva 《Cell and Tissue Biology》2014,8(1):61-67
Thoracic aortic aneurysm (TAA) develops as a result of complex sequential events that dynamically alter the structure and composition of the aortic vascular extracellular matrix (ECM). The main cellular elements that alter the composition of aortic wall are smooth muscle cells (SMCs). The purpose of the present work was to study alterations of smooth muscle cell functions derived from the patients with TAA and from healthy donors. Since it is believed that TAA associates with bicuspid aortic valve (BAV) and with tricuspid aortic valve (TAV) differed in their pathogenesis, we have compared SMCs and tissue samples from BAV and TAV patients and healthy donors. The comparison was done by several parameters: SMC growth, migration and apoptotic dynamics, metalloproteinase MMP2 and MMP9 activity (zymography), and elastin, collagen, and fibrillin content (Western blot) in both tissue samples and cultured SMCs. Proliferation of BAV and TAV SMCs was decreased and migration ability in scratch tests was increased in TAV-derived SMCs compared to donor cells. BAV-cells migration ability was not changed compared to donor SMCs. Elastin content was decreased in TAA SMCs, whereas the content of fibrillin and collagen was not altered. At the same time, the elastin and collagen protein level was significantly higher in tissue samples of TAA patients than in donorderived samples. SMC proliferation and migration is differently affected in TAV and BAV-associated TAA that supports the idea on different nature of these two TAA groups. Our data also show that SMC functional properties are altered in TAA patients and these alterations could play a significant role in the disease pathogenesis. 相似文献
18.
Chandrasekar B Mummidi S Mahimainathan L Patel DN Bailey SR Imam SZ Greene WC Valente AJ 《The Journal of biological chemistry》2006,281(22):15099-15109
19.
Daniel J. Angelini Qingning Su Irina A. Kolosova Chunling Fan John T. Skinner Kazuyo Yamaji-Kegan Michael Collector Saul J. Sharkis Roger A. Johns 《PloS one》2010,5(6)