PPARγ modulates vascular smooth muscle cell phenotype via a protein kinase G-dependent pathway and reduces neointimal hyperplasia after vascular injury View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-11-29

AUTHORS

Han-Mo Yang, Baek-Kyung Kim, Ju-Young Kim, Yoo-Wook Kwon, Sooryeonhwa Jin, Joo-Eun Lee, Hyun-Jai Cho, Hae-Young Lee, Hyun-Jae Kang, Byung-Hee Oh, Young-Bae Park, Hyo-Soo Kim

ABSTRACT

Vascular smooth muscle cells (VSMCs) undergo phenotypic changes in response to vascular injury such as angioplasty. Protein kinase G (PKG) has an important role in the process of VSMC phenotype switching. In this study, we examined whether rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-γ agonist, could modulate VSMC phenotype through the PKG pathway to reduce neointimal hyperplasia after angioplasty. In vitro experiments showed that rosiglitazone inhibited the phenotype change of VSMCs from a contractile to a synthetic form. The platelet-derived growth factor (PDGF)-induced reduction of PKG level was reversed by rosiglitazone treatment, resulting in increased PKG activity. This increased activity of PKG resulted in phosphorylation of vasodilator-stimulated phosphoprotein at serine 239, leading to inhibited proliferation of VSMCs. Interestingly, rosiglitazone did not change the level of nitric oxide (NO) or cyclic guanosine monophosphate (cGMP), which are upstream of PKG, suggesting that rosiglitazone influences PKG itself. Chromatin immunoprecipitation assays for the PKG promoter showed that the activation of PKG by rosiglitazone was mediated by the increased binding of Sp1 on the promoter region of PKG. In vivo experiments showed that rosiglitazone significantly inhibited neointimal formation after balloon injury. Immunohistochemistry staining for calponin and thrombospondin showed that this effect of rosiglitazone was mediated by modulating VSMC phenotype. Our findings demonstrate that rosiglitazone is a potent modulator of VSMC phenotype, which is regulated by PKG. This activation of PKG by rosiglitazone results in reduced neointimal hyperplasia after angioplasty. These results provide important mechanistic insight into the cardiovascular-protective effect of PPARγ. More... »

PAGES

e65

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/emm.2013.112

DOI

http://dx.doi.org/10.1038/emm.2013.112

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1004651461

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24287871


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28 schema:description Vascular smooth muscle cells (VSMCs) undergo phenotypic changes in response to vascular injury such as angioplasty. Protein kinase G (PKG) has an important role in the process of VSMC phenotype switching. In this study, we examined whether rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-γ agonist, could modulate VSMC phenotype through the PKG pathway to reduce neointimal hyperplasia after angioplasty. In vitro experiments showed that rosiglitazone inhibited the phenotype change of VSMCs from a contractile to a synthetic form. The platelet-derived growth factor (PDGF)-induced reduction of PKG level was reversed by rosiglitazone treatment, resulting in increased PKG activity. This increased activity of PKG resulted in phosphorylation of vasodilator-stimulated phosphoprotein at serine 239, leading to inhibited proliferation of VSMCs. Interestingly, rosiglitazone did not change the level of nitric oxide (NO) or cyclic guanosine monophosphate (cGMP), which are upstream of PKG, suggesting that rosiglitazone influences PKG itself. Chromatin immunoprecipitation assays for the PKG promoter showed that the activation of PKG by rosiglitazone was mediated by the increased binding of Sp1 on the promoter region of PKG. In vivo experiments showed that rosiglitazone significantly inhibited neointimal formation after balloon injury. Immunohistochemistry staining for calponin and thrombospondin showed that this effect of rosiglitazone was mediated by modulating VSMC phenotype. Our findings demonstrate that rosiglitazone is a potent modulator of VSMC phenotype, which is regulated by PKG. This activation of PKG by rosiglitazone results in reduced neointimal hyperplasia after angioplasty. These results provide important mechanistic insight into the cardiovascular-protective effect of PPARγ.
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36 PKG levels
37 PKG pathway
38 PKG promoter
39 PPARγ
40 Sp1
41 VSMC phenotype
42 VSMC phenotype switching
43 activation
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45 activity
46 activity of PKG
47 agonists
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52 calponin
53 cardiovascular protective effects
54 cell phenotype
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57 chromatin immunoprecipitation
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64 factors
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66 form
67 formation
68 growth factor
69 guanosine monophosphate
70 hyperplasia
71 immunohistochemistry
72 immunoprecipitation
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74 important role
75 increased PKG activity
76 influences PKG
77 inhibited proliferation
78 injury
79 insights
80 kinase G
81 levels
82 mechanistic insights
83 modulator
84 monophosphate
85 muscle cell phenotype
86 muscle cells
87 neointimal formation
88 neointimal hyperplasia
89 nitric oxide
90 oxide
91 pathway
92 peroxisome proliferator-activated receptor
93 phenotype
94 phenotype changes
95 phenotype switching
96 phenotypic changes
97 phosphoprotein
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99 platelet-derived growth factor
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101 process
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103 proliferator-activated receptor
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106 protein kinase G
107 receptors
108 reduction
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110 response
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112 role
113 rosiglitazone
114 rosiglitazone influences PKG
115 rosiglitazone results
116 rosiglitazone treatment
117 serine 239
118 smooth muscle cell phenotype
119 smooth muscle cells
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126 vascular smooth muscle cell phenotype
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