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1.
Sci Rep ; 6: 36979, 2016 11 11.
Article in English | MEDLINE | ID: mdl-27833146

ABSTRACT

In spite of its great success in reducing restenosis, drug-eluting stent (DES) has unfavorable aspects such as stent thrombosis and delayed re-endothelialization. We examined the effects of PKG activation by Exisulind on neointimal formation, platelet aggregation, and re-endothelialization. Exisulind significantly reduced VSMCs viability, cell cycle progression, migration, and neointimal hyperplasia after vascular injury in rat carotid arteries. Interestingly, in contrast to the effect on VSMC viability, Exisulind did not reduce the viability of endothelial cells. Increased PKG activity by Exisulind inhibited PDGF-stimulated phenotype change of VSMCs from a contractile to a synthetic form. Conversely, the use of PKG inhibitor or gene transfer of dominant-negative PKG reversed the effects of Exisulind, resulting in the increased viability of VSMCs and neointimal formation. In addition, Exisulind facilitated the differentiation of peripheral blood mononuclear cells to endothelial lineage via PKG pathway, while inhibiting to VSMCs lineage, which was correlated with the enhanced re-endothelialization in vivo. Finally, Exisulind reduced platelet aggregation, which was mediated via PKG activation. This study demonstrated that Exisulind inhibits neointimal formation and platelet aggregation while increasing re-endothelialization via PKG pathway. These findings suggest that Exisulind could be a promising candidate drug of DES for the prevention of restenosis without other complications.


Subject(s)
Cyclic GMP-Dependent Protein Kinases/metabolism , Endothelial Cells/cytology , Hyperplasia/drug therapy , Neointima/drug therapy , Sulindac/analogs & derivatives , Animals , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Humans , Hyperplasia/metabolism , Male , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/cytology , Myocytes, Smooth Muscle/metabolism , Neointima/metabolism , Platelet-Derived Growth Factor/pharmacology , Rats , Sulindac/pharmacology , Transcriptional Activation
2.
Exp Mol Med ; 45: e65, 2013 Nov 29.
Article in English | MEDLINE | ID: mdl-24287871

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.


Subject(s)
Aorta/pathology , Cyclic GMP-Dependent Protein Kinases/metabolism , Myocytes, Smooth Muscle/metabolism , PPAR gamma/metabolism , Tunica Intima/pathology , Vascular System Injuries/metabolism , Animals , Aorta/injuries , Aorta/metabolism , Calcium-Binding Proteins/genetics , Calcium-Binding Proteins/metabolism , Cell Proliferation , Cyclic GMP/metabolism , Cyclic GMP-Dependent Protein Kinases/genetics , Hyperplasia/metabolism , Microfilament Proteins/genetics , Microfilament Proteins/metabolism , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/drug effects , Nitric Oxide/metabolism , PPAR gamma/agonists , Promoter Regions, Genetic , Rats , Rats, Sprague-Dawley , Rosiglitazone , Sp1 Transcription Factor/metabolism , Thiazolidinediones/pharmacology , Thrombospondins/genetics , Thrombospondins/metabolism , Tunica Intima/metabolism , Vascular System Injuries/pathology , Calponins
3.
Biomaterials ; 33(35): 8917-27, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22981075

ABSTRACT

Vascular endothelial-cadherin (VE-cadherin) is exclusively expressed on the late endothelial progenitor cells (EPC). Therefore, VE-cadherin could be an ideal target surface molecule to capture circulating late EPC. In the present study, we evaluated whether anti-VE-cadherin antibody-coated stents (VE-cad stents) might accelerate endothelial recovery and reduce neointimal formation more than anti-CD34 antibody-coated stents (CD34 stents) through the superior ability to capture the late EPC. The stainless steel stents were coated with anti-human VE-cadherin antibodies or anti-human CD34 antibodies under the same condition. In vitro, VE-cad stents showed higher number of adhering EPC (823.6 ± 182.2 versus 379.2 ± 137.2 cells per HPF, p < 0.001). VE-cad stents also demonstrated better specific capturing of cells with endothelial lineage markers than CD34 stents did in flow cytometric analysis. VE-cad stents showed more effective re-endothelialization after 1 h, 24 h, and 3 days in vivo. At 42 days, VE-cad stents demonstrated significantly smaller neointima area (0.92 ± 0.38 versus 1.24 ± 0.41 mm(2), p = 0.002) and significantly lower PCNA positive cells in neointima (1684.8 ± 658.8/mm(2) versus 2681.7 ± 375.1/mm(2), p = 0.008), compared with CD34 stents. In conclusion, VE-cad stents captured EPC and endothelial cells more selectively in vitro, accelerated re-endothelialization over stents, and reduced neointimal formation in vivo, compared with CD34 stents.


Subject(s)
Antibodies/chemistry , Antigens, CD34/chemistry , Antigens, CD/chemistry , Cadherins/chemistry , Neointima/metabolism , Stents , Cell Proliferation , Coated Materials, Biocompatible , Endothelial Cells/cytology , Endothelium/metabolism , Humans , Leukocytes, Mononuclear/chemistry , Stem Cells/cytology , Stem Cells/metabolism
4.
PLoS One ; 6(11): e28327, 2011.
Article in English | MEDLINE | ID: mdl-22140576

ABSTRACT

The role and underlying mechanisms of rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, on myocardial infarction are poorly understood. We investigated the effects of this PPAR-γ agonist on the expression of tissue factor (TF), a primary molecule for thrombosis, and elucidated its underlying mechanisms. The PPAR-γ agonist inhibited TF expression in response to TNF-α in human umbilical vein endothelial cells, human monocytic leukemia cell line, and human umbilical arterial smooth muscle cells. The overexpression of TF was mediated by increased phosphorylation of mitogen-activated protein kinase (MAPK), which was blocked by the PPAR-γ agonist. The effective MAPK differed depending on each cell type. Luciferase and ChIP assays showed that transcription factor, activator protein-1 (AP-1), was a pivotal target of the PPAR-γ agonist to lower TF transcription. Intriguingly, two main drugs for drug-eluting stent, paclitaxel or rapamycin, significantly exaggerated thrombin-induced TF expression, which was also effectively blocked by the PPAR-γ agonist in all cell types. This PPAR-γ agonist did not impair TF pathway inhibitor (TFPI) in three cell types. In rat balloon injury model (Sprague-Dawley rats, n = 10/group) with continuous paclitaxel infusion, the PPAR-γ agonist attenuated TF expression by 70±5% (n = 4; P<0.0001) in injured vasculature. Taken together, rosiglitazone reduced TF expression in three critical cell types involved in vascular thrombus formation via MAPK and AP-1 inhibitions. Also, this PPAR-γ agonist reversed the paclitaxel-induced aggravation of TF expression, which suggests a possibility that the benefits might outweigh its risks in a group of patients with paclitaxel-eluting stent implanted.


Subject(s)
Catheterization , PPAR gamma/agonists , Paclitaxel/administration & dosage , Thiazolidinediones/pharmacology , Thromboplastin/metabolism , Animals , Disease Models, Animal , Enzyme Activation/drug effects , Gene Expression Regulation/drug effects , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Infusions, Intra-Arterial , Lipoproteins/metabolism , Mitogen-Activated Protein Kinases/metabolism , Models, Biological , Monocytes/drug effects , Monocytes/metabolism , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Phosphorylation/drug effects , Promoter Regions, Genetic/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Rosiglitazone , Sirolimus/pharmacology , Thromboplastin/genetics , Umbilical Arteries/pathology
5.
Cardiovasc Res ; 82(3): 550-60, 2009 Jun 01.
Article in English | MEDLINE | ID: mdl-19234301

ABSTRACT

AIMS: Inflammation, and the subsequent proliferative activity of vascular smooth muscle cells (VSMCs), is one of the major pathophysiological mechanisms associated with neointimal hyperplasia following vascular injury. Although sulfasalazine (SSZ) has been used as an anti-inflammatory and immune-modulatory agent in various inflammatory diseases, its primary targets and therapeutic effects on vascular disease have not yet been determined. We investigated whether SSZ could suppress VSMC growth and prevent neointimal hyperplasia. METHODS AND RESULTS: SSZ was found to have pro-apoptotic and anti-proliferative activity in cultured VSMCs. Unexpectedly, these effects were not mediated by nuclear factor kappa B (NF-kappaB) inhibition, which has been suggested to be the anti-inflammatory mechanism associated with the effects of SSZ. Instead, cell-cycle arrest of the VSMCs was observed, which was mediated by induction of haem oxygenase-1 (HO-1) followed by an increased expression of p21(waf1/Cip1). The underlying mechanism for SSZ-induced HO-1 expression was by reactive oxygen species (ROS)-dependent nuclear translocation and activation of nuclear factor erythroid-2-related factor 2 (Nrf2). In a rat carotid artery balloon injury model, administration of SSZ significantly suppressed neointimal growth. In a series of reverse experiments, inhibition of HO-1 by shRNA, ROS by N-acetylcysteine (NAC) or Nrf2 by dominant-negative Nrf2 abrogated the beneficial effects of SSZ. CONCLUSION: Our data demonstrate that SSZ inhibits VSMC proliferation in vitro and in vivo through a novel signalling pathway and may be a promising therapeutic option for the treatment of proliferative vascular disease.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Graft Occlusion, Vascular/prevention & control , Heme Oxygenase-1/metabolism , NF-E2-Related Factor 2/metabolism , Sulfasalazine/therapeutic use , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antioxidants/metabolism , Apoptosis/drug effects , Carotid Artery Diseases/prevention & control , Carotid Artery, Common/pathology , Cell Proliferation/drug effects , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Gene Expression Regulation , Hyperplasia/prevention & control , Muscle, Smooth, Vascular/drug effects , Myocytes, Smooth Muscle/drug effects , NF-kappa B/metabolism , Oxidative Stress/drug effects , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Sulfasalazine/pharmacology , Tumor Necrosis Factor-alpha/metabolism
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