UMLS:C0004153 - FACTA Search

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phenotypic modulation of smooth muscle cells (SMCs) plays an integral role in atherosclerosis, hypertension and leiomyogenic tumorigenicity. The morphological, functional, and biochemical characteristics of SMCs in different phenotypes such as differentiated and dedifferentiated states have been well studied. Recent researches have focused on the expressional regulation of SMC-specific marker genes in association with phenotypic modulation of SMCs. The SMC-specific marker genes are regulated at the levels of transcription and splicing. The caldesmon, smooth muscle myosin heavy chain, alpha-smooth muscle actin, calponin, SM22, alpha- and beta-tropomyosins, and alpha1 integrin genes are transcriptionally regulated; transcription of these genes except for the alpha-smooth muscle actin gene is upregulated in differentiated SMCs, but is downregulated in dedifferentiated SMCs. The expression pattern of alpha-smooth muscle actin is opposite in vascular and visceral SMCs. In almost all promoter regions of these genes, the CArG box and serum response factor (SRF) are involved in as the positive cis-element and the trans-acting factor, respectively. Isoform changes of caldesmon, alpha-tropomyosin, vinculin/metavinculin, and smooth muscle myosin heavy chain are regulated by alternative splicing in a SMC phenotype-dependent manner. Among them, isoform interconversions of caldesmon and alpha-tropomyosin are completely coordinated with phenotype of SMCs. The purpose of this paper is to summarize current knowledge of the expressional regulation of SMC-specific marker genes in different phenotypes of SMCs.
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PMID:Expressional regulation of smooth muscle cell-specific genes in association with phenotypic modulation. 1009 77

Cyclic GMP, produced in response to nitric oxide and natriuretic peptides, is a key regulator of vascular smooth muscle cell contractility, growth, and differentiation, and is implicated in opposing the pathophysiology of hypertension, cardiac hypertrophy, atherosclerosis, and vascular injury/restenosis. cGMP regulates gene expression both positively and negatively at transcriptional as well as at posttranscriptional levels. cGMP-regulated transcription factors include the cAMP-response element binding protein CREB, the serum response factor SRF, and the nuclear factor of activated T cells NF/AT. cGMP can regulate CREB directly, through phosphorylation by cGMP-dependent protein kinase, or indirectly, through activation of mitogen-activated protein kinase pathways; regulation of SRF and NF/AT by cGMP is indirect, through modulation of RhoA and calcineurin signaling, respectively. Downregulation of the RNA-binding protein HuR by cGMP leads to destabilization of guanylate cyclase mRNA, but this posttranscriptional mechanism may affect many more cGMP-regulated genes. In this review, we discuss the role of cGMP-regulated gene expression in (patho)physiological processes most relevant to the cardiovascular system, such as regulation of vascular tone, cardiac hypertrophy, phenotypic modulation of vascular smooth muscle cells, and regulation of cell proliferation and apoptosis.
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PMID:Regulation of gene expression by cyclic GMP. 1464 34

Myofibroblasts play important roles in a variety of developmental and pathological processes, such as vascular remodeling, atherosclerosis and wound healing. In this study, we used the TGF-beta1-treated 10T1/2 cells as an in vitro model to understand how Smad-mediated TGF-beta1 signals regulate SM22 promoter transcription during myofibroblast differentiation. We found that TGF-beta1 transiently induces SRF and SM22 transcription, and that this process is accompanied by transient increases of SRF and Smad3 binding to the SM22 promoter. Interestingly, Smad3, not Smad2, is the primary mediator for TGF-beta1-induced transactivation of the SM22 promoter, while Smad6 and Smad7 repress such a transactivation. Smad3 can bind to a Smad-binding element (SBE) in the first exon of SM22, and directly associate with the SRF complex in response to TGF-beta1 treatment. Moreover, Smad3 and I-Smads regulate the SM22 promoter through CArG box-dependent transcription using dominant-negative SRF mutants and SRF-VP16. Although SBE as well as CArG boxes and TGF-beta control element are all important for the SM22 promoter activities, the promoters with mutations at either one or all of them still respond to TGF-beta1 treatment. Consistently, TGF-beta1 stimulates SM22 transcription in Smad3 null mouse embryonic fibroblasts. These findings provide the first evidence that Smad3 directly links TGF-beta1 signaling to an SRF-associated regulatory network in controlling SM22 transcription; it also implies that TGF-beta1 regulates the SM22 promoter via Smad3-dependent and Smad3-independent pathways.
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PMID:Interaction of Smad3 and SRF-associated complex mediates TGF-beta1 signals to regulate SM22 transcription during myofibroblast differentiation. 1465 67

Intimal thickening is an early phase of atherosclerosis characterized by differentiation of plaque smooth muscle cells (SMCs) from a contractile to a synthetic phenotype. We used laser microdissection (LMD) plus real-time RT-PCR to quantify mRNAs for calponin-1 and smoothelin, markers of the contractile phenotype, and for serum response factor (SRF), a regulator of SMC differentiation, in intimal and medial SMCs of human coronary arteries with intimal thickening. RNA expression was also analyzed by ISH and protein expression was detected by IHC. LMD plus RT-PCR found similar levels of SRF mRNA in intimal and medial SMCs, while medial mRNA levels for calponin-1 and smoothelin were higher. ISH confirmed that smoothelin mRNA levels in media exceeded those in intima, whereas SRF mRNA levels were similar at both sites. For calponin-1 and smoothelin, protein levels mirrored respective mRNA levels. By contrast, more medial than intimal SRF protein was present. Our results indicate that intimal SMCs exhibit a largely synthetic phenotype, perhaps reflecting lower intimal levels of SRF protein; ISH and LMD plus real-time RT-PCR provide comparable results; as a valuable alternative to ISH, LMD plus RT-PCR allows parallel measurement of several transcripts; and tissue gene expression studies must measure both protein and mRNA levels.
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PMID:Laser microdissection-based analysis of mRNA expression in human coronary arteries with intimal thickening. 1550 46

Understanding the mechanism of smooth muscle cell (SMC) differentiation will provide the foundation for elucidating SMC-related diseases such as atherosclerosis, restenosis, and asthma. Recent studies have demonstrated that the interaction of SRF with the co-activator myocardin is a critical determinant of smooth muscle development. It has been proposed that the specific transcriptional activation of smooth muscle-restricted genes (as opposed to other SRF-dependent genes) by myocardin results from the presence of multiple CArG boxes in smooth muscle genes that facilitate myocardin homodimer formation. This proposal was further tested in the current study. Our results show that the SMC-specific telokin promoter, which contains only a single CArG box, is strongly activated by myocardin. Furthermore, myocardin and a dimerization defective mutant myocardin induce expression of endogenous telokin but not c-fos in 10T1/2 fibroblast cells. Knocking down myocardin by small interfering RNA decreased telokin promoter activity and expression in A10 SMCs. A series of telokin and c-fos promoter chimeric and mutant reporter genes was generated to determine the mechanisms responsible for the promoter-specific effects of myocardin. Data from these experiments demonstrated that the ets binding site in the c-fos promoter partially blocks the activation of this promoter by myocardin. However, the binding of ets factors alone was not sufficient to explain the promoter-specific effects of myocardin. Elements 3' of the CArG box in the c-fos promoter act in concert with the ets binding site to block the ability of myocardin to activate the promoter. Conversely, elements 5' and 3' of the CArG box in the telokin promoter act in concert with the CArG box to facilitate myocardin stimulation of the promoter. Together these data suggest that the promoter specificity of myocardin is dependent on complex combinatorial interactions of multiple cis elements and their trans binding factors.
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PMID:Mechanisms responsible for the promoter-specific effects of myocardin. 1565 56

Understanding the mechanism of smooth muscle cell (SMC) differentiation will provide the foundation for elucidating SMC-related diseases, such as atherosclerosis, restenosis, and asthma. In the current study, overexpression of Elk-1 in SMCs down-regulated expression of several endogenous smooth muscle-restricted proteins, including telokin, SM22alpha, and smooth muscle alpha-actin. In contrast, down-regulation of endogenous Elk-1 in smooth muscle cells increased the expression of only telokin and SM22alpha, suggesting that smooth muscle-specific promoters are differentially sensitive to the inhibitory effects of Elk-1. Consistent with this, overexpression of the DNA binding domain of Elk-1, which acts as a dominant-negative protein by displacing endogenous Elk-1, enhanced the expression of telokin and SM22alpha without affecting expression of smooth muscle alpha-actin. Elk-1 suppressed the activity of smooth muscle-restricted promoters, including the telokin promoter that does not contain a consensus Elk-1 binding site, through its ability to block myocardin-induced activation of the promoters. Gel mobility shift and chromatin immunoprecipitation assays revealed that Elk-1 binds to a nonconsensus binding site in the telokin promoter and Elk-1 binding is dependent on serum response factor (SRF) binding to a nearby CArG box. Although overexpression of the SRF-binding B-box domain of Elk-1 is sufficient to repress the myocardin activation of the telokin promoter, this repression is not as complete as that seen with an Elk-1 fragment that includes the DNA binding domain. In addition, reporter gene assays demonstrate that an intact Elk-1 binding site in the telokin promoter is required for Elk-1 to maximally inhibit promoter activity. Together, these data suggest that the differential sensitivity of smooth muscle-specific genes to inhibition by Elk-1 may play a role in the complex changes in smooth muscle-specific protein expression that are observed under pathological conditions.
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PMID:Smooth muscle-specific genes are differentially sensitive to inhibition by Elk-1. 1626 Jun 3

Phenotypic change of vascular smooth muscle cells (VSMCs) from a differentiated to a dedifferentiated state accompanies the early stage of atherosclerosis and restenosis. Although much progress has been made in determining the molecular mechanisms involved in VSMC dedifferentiation, research on VSMC redifferentiation is hindered by the lack of an appropriate complete redifferentiation model. We established an in vitro model of redifferentiation by using postconfluent VSMCs from human umbilical artery. We demonstrated that serum-deprived VSMCs are capable of complete redifferentiation. After serum deprivation, postconfluent cultured human umbilical VSMCs became elongated and spindle shaped, with elevation of myofilament density, and reacquired contraction. Expressions of VSMC-specific contractile proteins, such as smooth muscle (SM) alpha-actin, SM-myosin heavy chain, calponin, and SM 22alpha, were increased and reached the levels in differentiated cells after serum deprivation. To determine the molecular mechanism of the phenotypic reversion, the levels of expression, phosphorylation, and binding activity of serum response factor (SRF), a key phenotypic modulator for VSMCs, were measured. The results showed that SRF binding activity with CArG motif was significantly increased after serum deprivation, whereas no changes were found in SRF expression and phosphorylation. The increased SRF binding activity was accompanied by an increase in expression of its coactivators such as myocardin. Furthermore, the phenotypic reversion was markedly inhibited by decoy double-strand oligodeoxynucleotides containing SM alpha-actin CArG motif, which was able to competitively bind to SRF. The results suggested that serum deprivation results in redifferentiation of human umbilical VSMCs. This novel model of VSMC phenotypic reversion should be valuable for research on vascular disease.
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PMID:Serum deprivation results in redifferentiation of human umbilical vascular smooth muscle cells. 1646 1

The phenotype of smooth muscle cells (SMCs) plays an important role in vascular function in health and disease. We investigated the mechanism of modulation of SMC phenotype (from contractile to synthetic) induced by the synergistic action of a growth factor (platelet-derived growth factor, PDGF-BB) and a cytokine (interleukin, IL-1beta). Human aortic SMCs grown on polymerized collagen showed high expression levels of contractile markers (smooth muscle alpha-actin, myosin heavy chain, and calponin). These levels were not significantly affected by PDGF-BB and IL-1beta individually, but decreased markedly after the combined usage of PDGF-BB and IL-1beta. PDGF/IL-1beta costimulation also induced a sustained phosphorylation of Akt and p70 ribosomal S6 kinase (p70S6K). The effects of PDGF/IL-1beta costimulation on contractile marker expression and Akt and p70S6K phosphorylation were blocked by the phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 and by adenovirus expressing a dominant-negative Akt, and they were mimicked by constitutively active Akt. PDGF-BB/IL-1beta induced a sustained phosphorylation of PDGF receptor (PDGFR)-beta and its association with IL-1 receptor (IL-1R1). Such activation and association of receptors were blocked by a PDGFR-beta neutralizing antibody (AF385), an IL-1R1 antagonist (IL-1ra), as well as a specific inhibitor of PDGFR-beta phosphorylation (AG1295); these agents also eliminated the PDGF-BB/IL-1beta-induced signaling and phenotypic modulation. PDGF-BB/IL-1beta inhibited the polymerized collagen-induced serum response factor DNA binding activity in the nucleus, and this effect was mediated by the PDGFR-beta/IL-1R1 association and phosphatidylinositol 3-kinase/Akt/p70S6K pathway. Our findings provide insights into the mechanism of SMC phenotypic modulation from contractile to synthetic, e.g., in atherosclerosis.
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PMID:Synergistic roles of platelet-derived growth factor-BB and interleukin-1beta in phenotypic modulation of human aortic smooth muscle cells. 1647 12

During the onset and progression of atherosclerosis, the vascular smooth muscle cell (VSMC) phenotype changes from differentiated to dedifferentiated, and in some cases, this change is accompanied by osteogenic transition, resulting in vascular calcification. One characteristic of dedifferentiated VSMCs is the down-regulation of smooth muscle cell (SMC) marker gene expression. Bone morphogenetic proteins (BMPs), which are involved in the induction of osteogenic gene expression, are detected in calcified vasculature. In this study, we found that the BMP2-, BMP4-, and BMP6-induced expression of Msx transcription factors (Msx1 and Msx2) preceded the down-regulation of SMC marker expression in cultured differentiated VSMCs. Either Msx1 or Msx2 markedly reduced the myocardin-dependent promoter activities of SMC marker genes (SM22alpha and caldesmon). We further investigated interactions between Msx1 and myocardin/serum response factor (SRF)/CArG-box motif (cis element for SRF) using coimmunoprecipitation, gel-shift, and chromatin immunoprecipitation assays. Our results showed that Msx1 or Msx2 formed a ternary complex with SRF and myocardin and inhibited the binding of SRF or SRF/myocardin to the CArG-box motif, resulting in inhibition of their transcription.
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PMID:Bone morphogenetic protein-induced MSX1 and MSX2 inhibit myocardin-dependent smooth muscle gene transcription. 1703 Jun 28

Atherosclerosis is an inflammatory disease that preferentially forms at hemodynamically compromised regions of altered shear stress patterns. Endothelial cells (EC) and smooth muscle cells (SMC) undergo phenotypic modulation during atherosclerosis. An in vitro coculture model was developed to determine the role of hemodynamic regulation of EC and SMC phenotypes in coculture. Human ECs and SMCs were plated on a synthetic elastic lamina and human-derived atheroprone, and atheroprotective shear stresses were imposed on ECs. Atheroprone flow decreased genes associated with differentiated ECs (endothelial nitric oxide synthase, Tie2, and Kruppel-like factor 2) and SMCs (smooth muscle alpha-actin and myocardin) and induced a proinflammatory phenotype in ECs and SMCs (VCAM-1, IL-8, and monocyte chemoattractant protein-1). Atheroprone flow-induced changes in SMC differentiation markers were regulated at the chromatin level, as indicated by decreased serum response factor (SRF) binding to the smooth muscle alpha-actin-CC(a/T)(6)GG (CArG) promoter region and decreased histone H(4) acetylation. Conversely, SRF and histone H(4) acetylation were enriched at the c-fos promoter in SMCs. In the presence of atheroprotective shear stresses, ECs aligned with the direction of flow and SMCs aligned more perpendicular to flow, similar to in vivo vessel organization. These results provide a novel mechanism whereby modulation of the EC phenotype by hemodynamic shear stresses, atheroprone or atheroprotective, play a critical role in mechanical-transcriptional coupling and regulation of the SMC phenotype.
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PMID:Atherosclerosis-prone hemodynamics differentially regulates endothelial and smooth muscle cell phenotypes and promotes pro-inflammatory priming. 1791 48

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