Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular smooth muscle cells (VSMCs) are involved in a number of vascular disease processes including hypertension and atherosclerosis. However, their role in the pathogenesis of vascular disease is largely undetermined. We and others have studied rat VSMCs in cell culture as a model for VSMC behaviour in vivo. In recent experiments we have applied molecular biological techniques to compare genes expressed by normal contractile VSMCs with those expressed by VSMCs which have undergone several passages in cell culture. Using differential screening of a cDNA library derived from cultured rat aortic VSMC RNA we identified seven genes which are preferentially expressed by contractile VSMCs; alpha-smooth muscle actin, gamma-smooth muscle actin, calponin, phospholamban, tropoelastin, SM22 alpha and CHIP28, and two which are preferentially expressed in passaged cells which have down-regulated their contractile proteins; osteopontin (OP) and matrix Gla protein (MGP). In situ hybridization studies have confirmed that calponin and SM22 alpha, are highly expressed by medial VSMCs in human coronary arteries with little or no expression in the atheromatous intima whilst the converse is true for OP and MGP. Studies by ourselves and others have confirmed that OP is a marker for proliferating rat VSMCs both in vitro and in vivo. However, the evidence that OP is expressed by proliferating human VSMCs is less convincing.
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PMID:Gene expression and vascular smooth muscle cell phenotype. 758 79

Phenotypic change of the smooth muscle cell (SMC) is implicated in normal development as well as several pathological processes including atherosclerosis. In general, differentiation SMCs show contractile responses to different exogenous stimuli and are inactive in mitosis, while undifferentiated or dedifferentiated SMCs show a mitogenic response and are not contractible. In the present review, we describe structural and functional aspects of the phenotypic change of SMCs with special reference to their role in atherogenesis. SMCs derived from atherosclerotic intimal lesions (intimal SMCs) show more amplified growth potential and chemotactic activity than medial SMCs; and furthermore, they require a macrophage-like phenotype: uptake of modified low density lipoproteins through the scavenger receptor, which leads to high tendency toward foam cell formation. Platelet-derived growth factor, secreted from most of the cells existing in atherosclerotic plaques, is one of candidates that promote the formation of such a highly dedifferentiated intimal SMC. Clinical and experimental evidence supports the concept that an appearance of the pathological intimal SMCs is a key step for their abnormal proliferation in atheromatous lesions. Recent advances in characterization of the phenotype-specific molecular markers for SMC, such as myosin heavy chain, caldesmon, and calponin, are also described.
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PMID:[Phenotypic change of the smooth muscle cell and atherosclerosis]. 872 89

Phenotypic modulation of smooth muscle cells is closely associated with vasculogenesis, enterogenesis and some diseases such as atherosclerosis, hypertension and leiomyogenic tumorigenicity. During phenotypic modulation, smooth muscle cells change their morphology, cell function and biochemical characteristics. Recent studies have focused on the regulation mechanism of smooth muscle cell-specific genes at the levels of transcription and/or alternative splicing in a phenotype-dependent manner. Typical examples of such genes include caldesmon, alpha-tropomyosin, myosin heavy chain, SM22, calponin and alpha 1 integrin. Cell adhesion molecules and growth factors/cytokines also play a critical role for controlling phenotype of smooth muscle cells via signal transduction pathways such as phosphoinositide 3-kinase and mitogen-activated protein kinases.
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PMID:Molecular mechanism of phenotypic modulation of smooth muscle cells. 972 87

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

The monoclonal theory of atherosclerosis postulates that a certain subpopulation of vascular smooth muscle cells (VSMC) is selectively expanded in response to pathological stimuli thereby contributing to the formation of atherosclerotic plaques. VSMC cloning experiments will be important in characterizing the phenotypic composition of VSMC in atherosclerotic plaques. However, the difficulty in cloning human VSMC is well recognized. Here a technique is described that produced multiple clones from human saphenous vein. The clones could be divided into two categories based on their distinctly different morphology: (1) spindle-shaped; and, (2) epithelioid-shaped. Each clone expressed smooth muscle-a-actin and calponin, two smooth muscle-specific differentiation markers. The clonal study presented here reports for the first time that phenotypically heterogeneous smooth muscle cells coexist within human saphenous veins.
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PMID:A method to isolate morphologically distinct clones of smooth muscle cells from human saphenous vein. 1284 1

The dedifferentiation of vascular smooth muscle cells (VSMCs) plays a critical role in the progression of atherosclerosis and restenosis after angioplasty. Thus, factors that stimulate smooth muscle cell differentiation should be useful for therapy for these diseases. Previously, we found that l-ascorbic acid (L-Asc) induces the expression of smooth muscle-specific genes in a pluripotent bone marrow stromal cell line, TBR-B. This finding suggests that l-Asc stimulates the differentiation of smooth muscle cells. In the present study, we investigated the effects of l-Asc and its derivatives on the differentiation state of VSMCs in vitro and in vivo. l-Asc and its long-lasting derivatives stimulated the production of smooth muscle-specific myosin heavy chain-1 (SM1) and calponin 1 in a dose-dependent manner in rat cultured VSMCs, and the elevated production of SM1 and calponin 1 was maintained for at least 2 weeks. Moreover, oral administration of 3 g/kg of l-Asc to the balloon-injured rats induced a higher expression of SM1 and calponin 1 in the injured arteries compared with that from administration of the delivery vehicle alone. These data demonstrated new biologic activity, such as the stimulation of VSMC differentiation, of l-Asc and its long-lasting derivatives. In addition, these compounds may serve as useful tools for analysis of the differentiation of VSMCs and for therapy for vascular diseases.
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PMID:L-ascorbic acid stimulates expression of smooth muscle-specific markers in smooth muscle cells both in vitro and in vivo. 1463 96

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

Coronary artery blockage, due to cardiovascular disease, is routinely treated by either balloon-angioplasty or bypass surgery. The limited success of these clinical interventions is due at least in part to smooth muscle cell (SMC) proliferation. Here we show that heterogeneous nuclear ribonucleoprotein complex K (hnRNP-K) protein levels increase in SMC with response to serum stimulation in vitro, in the aortas from an animal model of atherosclerosis, and in occluded human vein segments. hnRNP-K is a multi-functional protein that has been studied primarily in cancer cells and has been suggested to play a role in cell cycle progression. We show that in untransformed, cultured SMC, hnRNP-K protein sub-cellular localization modulates through the cell cycle in both the cytoplasm and nucleus. Using cycloheximide, we observed that cytoplasmic accumulation of hnRNP-K protein at later time points in the cell cycle occurred with a concomitant decrease in nuclear hnRNP-K protein, suggesting a translocation of nuclear hnRNP-K protein to the cytoplasm. Also, because we did not observe an increase in hnRNP-K protein at early time points in the cell cycle in the presence of cycloheximide, we propose that the early increase in cytoplasmic hnRNP-K protein following serum stimulation is due to new hnRNP-K protein synthesis. When present in the cytoplasm, hnRNP-K is part of a multi-protein complex that consists of at least two other proteins, calponin and ERK1/2. Our findings from this study are intriguing because they suggest that cytoplasmic hnRNP-K in SMC is part of a signaling complex that may be involved in growth-stimulated post-transcriptional regulation.
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PMID:Compartmentalization of hnRNP-K during cell cycle progression and its interaction with calponin in the cytoplasm. 1596 5

Recent studies of cyclooxygenase-2 (COX-2) inhibitors suggest that the balance between thromboxane and prostacyclin is a critical factor in cardiovascular homeostasis. Disruption of prostacyclin signaling by genetic deletion of the receptor or by pharmacological inhibition of COX-2 is associated with increased atherosclerosis and restenosis after injury in animal models and adverse cardiovascular events in clinical trials (Vioxx). Human vascular smooth muscle cells (VSMC) in culture exhibit a dedifferentiated, migratory, proliferative phenotype, similar to what occurs after arterial injury. We report that the prostacyclin analog iloprost induces differentiation of VSMC from this synthetic, proliferative phenotype to a quiescent, contractile phenotype. Iloprost induced expression of smooth muscle (SM)-specific differentiation markers, including SM-myosin heavy chain, calponin, h-caldesmon, and SM alpha-actin, as determined by Western blotting and RT-PCR analysis. Iloprost activated cAMP/protein kinase A (PKA) signaling in human VSMC, and the cell-permeable cAMP analog 8-bromo-cAMP mimicked the iloprost-induced differentiation. Both myristoylated PKA inhibitor amide-(14-22) (PKI, specific PKA inhibitor), as well as ablation of the catalytic subunits of PKA by small interfering RNA, opposed the upregulation of contractile markers induced by iloprost. These data suggest that iloprost modulates VSMC phenotype via G(s) activation of the cAMP/PKA pathway. These studies reveal regulation of VSMC differentiation as a potential mechanism for the cardiovascular protective effects of prostacyclin. This provides important mechanistic insights into the induction of cardiovascular events with the use of selective COX-2 inhibitors.
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PMID:The prostacyclin receptor induces human vascular smooth muscle cell differentiation via the protein kinase A pathway. 1639 67

Up-regulation of the gap-junctional protein connexin43 (Cx43) in arterial smooth muscle cells (SMCs) features in response to injury and in atherosclerosis, in parallel with phenotypic transition to the synthetic state. TGF-beta1 is known to have a role in SMC differentiation and extracellular matrix (ECM) synthesis, key characteristics of phenotypic state. Here, we set out to examine the effects of TGF-beta1 on Cx43-gap junction expression in relation to SMC differentiation, ECM synthesis and growth. Cx43 expression was analysed by immunoconfocal microscopy and Western blotting in primary human aortic SMCs treated with TGF-beta1 over a 48-h period, with assessment of gap-junctional communication by cell-to-cell transfer of microinjected ethidium bromide. In parallel, synthetic activity was analysed by Northern blotting for ECM components alpha-1(I) and alpha1(III) procollagen transcripts, contractile differentiation was assessed by immunoconfocal microscopy and Western blotting of the markers smooth muscle alpha-actin, calponin and smooth muscle heavy chain isoform 1 (SM1), and growth was measured by BrdU incorporation. Our results demonstrate that TGF-beta1 significantly up-regulates Cx43 expression and intercellular communication, in concert with increased expression of alpha-actin, calponin and SM1. Concomitant with contractile protein expression, ECM synthesis was increased rather than decreased, TGF-beta1 inducing a significant up-regulation of both procollagen transcripts. These effects were independent of growth. We conclude that in human aortic SMCs, TGF-beta1 treatment leads to up-regulation of Cx43-mediated gap-junctional communication and increased synthetic activity yet, somewhat paradoxically, also enhanced contractile differentiation.
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PMID:Up-regulation of connexin43 correlates with increased synthetic activity and enhanced contractile differentiation in TGF-beta-treated human aortic smooth muscle cells. 1644 84


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