Redifferentiation of Smooth Muscle Cells After Coronary Angioplasty Determined via Myosin Heavy Chain Expression

Aikawa, Masamichi; Sakomura, Yasunari; Ueda, Makiko; Kimura, Kenjiro; Manabe, Ichiro; Ishiwata, Sugao; Komiyama, Nobuyuki; Yamaguchi, Hiroshi; Yazaki, Yoshio; Nagai, Ryozo

doi:10.1161/01.cir.96.1.82

Cited by 112 publications

(114 citation statements)

References 48 publications

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“…The present study is the first to show the suppressive effects of GLP-1 and GLP-1R agonists on PDGF-BB-induced proliferation and migration of human aortic VSMCs. The present study also showed that GLP-1 suppressed SMemb-positive VSMCs, a proliferative phenotype that acquires macrophage-like phagocytosis 20 . In previous studies we showed that chronic infusion of GLP-1 significantly prevented the infiltration of reported that exendin-4 suppresses murine VSMC proliferation and reduces intimal thickening after vascular injury 9 .…”

Section: Discussionsupporting

confidence: 76%

Glucagon-like Peptide-1 Suppresses the Proliferation and Migration of Vascular Smooth Muscle Cells: Implications for Preventive Effects on Atherosclerosis

Tomoyasu

Kim‐Kaneyama

Kohashi

et al. 2014

Showa Univ J Med Sci

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: Our group previously demonstrated the suppressive effect of glucagon-like peptide-1 GLP-1 on macrophage-driven atherosclerosis in apolipoprotein E-decient apoE / mice. In the present study we investigated the suppressive effect of GLP-1 on the atherogenic phenotype of vascular smooth muscle cells VSMCs in vivo using apoE / mice, and the proliferation and migration of human VSMCs in vitro. A 4-week infusion of GLP-1 in 17-week-old apoE / mice significantly reduced the proliferative VSMC phenotype stained with SMemb. Platelet-derived growth factor PDGF -BB signi cantly stimulated the proliferation of human aortic VSMCs by three fold. Both 0.1 and 1 nmol / l GLP-1 signi cantly suppressed the PDGF-induced VSMC proliferation, and this suppressive effect was significantly abolished by the GLP-1 receptor antagonist exendin 9−39 50 nmol / l . The GLP-1 receptor agonists liraglutide 100 nmol / l and exendin-4 100 nmol / l mimicked GLP-1, signi cantly suppressing PDGF-induced VSMC proliferation. PDGF-BB signi cantly stimulated the migration of human aortic VSMCs by 1.7 -fold, and this effect was signi cantly suppressed by 1 nmol / l GLP-1. These ndings suggest that GLP-1-related treatments may prevent the progression of atherosclerotic lesions by suppressing the proliferation and migration of VSMCs, which are characteristic features of atherosclerosis.

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Section: Discussionsupporting

confidence: 76%

Glucagon-like Peptide-1 Suppresses the Proliferation and Migration of Vascular Smooth Muscle Cells: Implications for Preventive Effects on Atherosclerosis

Tomoyasu

Kim‐Kaneyama

Kohashi

et al. 2014

Showa Univ J Med Sci

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“…We also detected USF binding activity to this E-box in nuclear extracts prepared from intact rat SM tissues. 2 Previous studies in our laboratory provided evidence for a role of USF in SM ␣-actin expression through E-boxes in the 5Ј-flanking sequences (27). Importantly, these E-boxes were required for transcription in vivo in transgenic mice (28).…”

Section: Expression Of the Sm-mhc Gene Is Regulated By Multiple Modulmentioning

confidence: 87%

“…Its expression is regulated precisely and dynamically during SMC differentiation and also during the formation and development of vascular diseases such as atherosclerosis (2,3). Therefore, studies on the mechanisms that regulate SM-MHC gene expression would be of great importance not only for understanding of transcriptional regulatory mechanisms in SMC differentiation but also for the understanding of the mechanisms of phenotypic modulation of SMCs in vascular diseases.…”

mentioning

confidence: 99%

The Smooth Muscle Myosin Heavy Chain Gene Exhibits Smooth Muscle Subtype-selective Modular Regulation in Vivo

Manabe

Owens

2001

Journal of Biological Chemistry

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Previous studies in our laboratory demonstrated that the transgene consisting of the ؊4.2 to ؉11.6 kilobase (kb) region of the smooth muscle (SM) myosin heavy chain (MHC) gene was expressed in virtually all SM tissue types in vivo in transgenic mice and that the multiple CArG elements within this region were differentially required in SMC subtypes, implying that the SM-MHC gene was controlled by multiple transcriptional regulatory modules. To investigate this hypothesis, we analyzed specific regulatory regions within the SM-MHC ؊4.2 to ؉11.6 kb region by a combination of deletion analyses of various SM-MHC transgenes as well as by DNaseI hypersensitivity assays and in vivo footprinting in intact SMC tissues. The results showed that SM-MHC transgene expression depended on a large number of required regulatory modules that were widely spread over the ؊4.2 to ؉11.6 region. Moreover, the results revealed several unexpected novel features of regulation of the SM-MHC gene including: 1) unique combinations of regulatory modules were required for SM-MHC expression in different SMC-subtypes; 2) repressor modules as well as activator modules were both critical for SMC specificity of the gene; 3) certain modules were required in certain contexts but were dispensable in others within a given SMC-subtype (i.e. the net activity of the module was determined by interaction between modules not simply by the sum of module activities); and 4) we identified a highly conserved 200-base pair transcriptional regulatory module at ؉8 kb that was required in the large arteries but dispensable in the coronary arteries and airways in transgenic mice and contained multiple potential cis-elements that were occupied by nuclear proteins in the intact aorta based on in vivo footprinting. Taken together, the results suggest a model of complex modular control of expression of the SM-MHC gene that varies between SMC subtypes. Moreover, the studies establish the possibility of designing derivatives of the SM-MHC promoter that might be used for targeting gene expression to specific SMC subtypes in vivo. Smooth muscle (SM)1 myosin heavy chain (MHC) is one of the best markers for smooth muscle cell (SMC) lineages (1). Its expression is regulated precisely and dynamically during SMC differentiation and also during the formation and development of vascular diseases such as atherosclerosis (2, 3). Therefore, studies on the mechanisms that regulate SM-MHC gene expression would be of great importance not only for understanding of transcriptional regulatory mechanisms in SMC differentiation but also for the understanding of the mechanisms of phenotypic modulation of SMCs in vascular diseases.We previously demonstrated that the SM-MHC genomic region from Ϫ4.2 to ϩ11.6 kb was capable of driving LacZ transgene expression in virtually all SMC subtypes in transgenic mice in vivo (4). In contrast, a LacZ transgene containing the Ϫ4.2 kb to ϩ88 bp of the SM-MHC gene was not expressed in any SMCs in multiple transgenic lines, indicating an absolute requirement of t...

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“…Aikawa and colleagues (4,5) found evidence for altered expression of SM MHC isoforms (SM-1 an SM-2) and SM ␣-actin in tissue samples obtained from autopsied patients and atherectomy specimens from patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Medial SMCs were positive for SM-1, SM-2, and SM ␣-actin.…”

Section: B Characterization Of the Smc Within Atherosclerotic Lesionmentioning

confidence: 99%

“…Intimal SMCs have been shown to undergo many additional changes including 1) increased DNA synthesis and expression of proliferation markers and cyclins such as proliferating cell nuclear antigen (PCNA) (77); 2) decreased expression of proteins characteristic of differentiated SMCs including SM MHCs (SM-1, SM-2), SM ␣-actin, SM22␣, smoothelin, h-caldesmin, desmin, calponin, and vinculin and increased ACLP and SMemb (4,129,130,138,183,257); 3) alterations in calcium handling and contractility (49,101,262); and 4) alterations in cell ultrastructure, including a general loss of myofilaments, which is replaced largely by synthetic organelles such as Golgi and rough endoplasmic reticulum, rounding of the cell from its typical elongated contractile morphology, and alterations in basement membrane (129,130,183). The preceding studies have been extended by Geary et al (72), who completed microarray-based profiling of gene expression patterns of SMCs in the neointima formed 4 wk after aortic grafting compared with those from the normal aorta in primates.…”

Section: B Characterization Of the Smc Within Atherosclerotic Lesionmentioning

confidence: 99%

Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease

Owens

Kumar²,

Wamhoff³

2004

Physiological Reviews

3,029

3,134

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The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms/processes that control differentiation of vascular smooth muscle cells (SMC) during normal development and maturation of the vasculature, as well as how these mechanisms/processes are altered in vascular injury or disease. A major challenge in understanding differentiation of the vascular SMC is that this cell can exhibit a wide range of different phenotypes at different stages of development, and even in adult organisms the cell is not terminally differentiated. Indeed, the SMC is capable of major changes in its phenotype in response to changes in local environmental cues including growth factors/inhibitors, mechanical influences, cell-cell and cell-matrix interactions, and various inflammatory mediators. There has been much progress in recent years to identify mechanisms that control expression of the repertoire of genes that are specific or selective for the vascular SMC and required for its differentiated function. One of the most exciting recent discoveries was the identification of the serum response factor (SRF) coactivator gene myocardin that appears to be required for expression of many SMC differentiation marker genes, and for initial differentiation of SMC during development. However, it is critical to recognize that overall control of SMC differentiation/maturation, and regulation of its responses to changing environmental cues, is extremely complex and involves the cooperative interaction of many factors and signaling pathways that are just beginning to be understood. There is also relatively recent evidence that circulating stem cell populations can give rise to smooth muscle-like cells in association with vascular injury and atherosclerotic lesion development, although the exact role and properties of these cells remain to be clearly elucidated. The goal of this review is to summarize the current state of our knowledge in this area and to attempt to identify some of the key unresolved challenges and questions that require further study.

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Redifferentiation of Smooth Muscle Cells After Coronary Angioplasty Determined via Myosin Heavy Chain Expression

Cited by 112 publications

References 48 publications

Glucagon-like Peptide-1 Suppresses the Proliferation and Migration of Vascular Smooth Muscle Cells: Implications for Preventive Effects on Atherosclerosis

Glucagon-like Peptide-1 Suppresses the Proliferation and Migration of Vascular Smooth Muscle Cells: Implications for Preventive Effects on Atherosclerosis

The Smooth Muscle Myosin Heavy Chain Gene Exhibits Smooth Muscle Subtype-selective Modular Regulation in Vivo

Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease

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