Interferon Regulatory Factor-1 Mediates PPARγ-Induced Apoptosis in Vascular Smooth Muscle Cells

Lin, Yiming; Zhu, Xiaojun; Mclntee, Farron L.; Xiao, Hailian; Zhang, Jifeng; Fu, Mingui; Chen, Yuqing E.

doi:10.1161/01.atv.0000109170.43400.2f

Cited by 33 publications

(27 citation statements)

References 68 publications

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“…This effect is likely to be mediated through the PPAR␥ receptor, because apoptotic trigger in vascular smooth muscle cell cultures induced by thiazolidinediones has been related to PPAR␥ by previous reports by our group (Redondo et al, 2005) and other groups (BishopBailey et al, 2002). Other PPAR␥ agonists, such as troglitazone, also induced apoptosis in vascular smooth muscle cells (Gouni-Berthold et al, 2001;Lin et al, 2004) and in several tumor cell lines by a mechanism of action involving the decrease in the expression of the antiapoptotic protein Bcl-2 (Yoshizawa et al, 2002;Shiau et al, 2005). In this context, we also observed that PIO treatment decreased protein level of Bcl-2 in cells from both nondiabetic and diabetic patients analyzed by Western blotting.…”

Section: Discussionsupporting

confidence: 67%

Pioglitazone Induces Apoptosis in Human Vascular Smooth Muscle Cells from Diabetic Patients Involving the Transforming Growth Factor-β/Activin Receptor-Like Kinase-4/5/7/Smad2 Signaling Pathway

Ruiz

Redondo

Gordillo‐Moscoso

et al. 2007

J Pharmacol Exp Ther

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Alterations in vascular wall remodeling are a typical complication in type 2 diabetes mellitus due to an imbalance between cell proliferation and apoptosis. In this context, we have previously shown that vascular smooth muscle cells (VSMC) from diabetic patients were resistant to induced apoptosis. Thiazolidinediones, such as pioglitazone, seem to exert direct antiatherosclerotic effects on type 2 diabetes. Here, we aimed to study whether pioglitazone was able to induce apoptosis in VSMC from diabetic patients (DP) and, if so, whether the transforming growth factor (TGF)-␤1/Smad-2 pathway was involved. We isolated human internal mammary artery VSMC from patients who had undergone coronary-artery bypass graft. Pioglitazone (100 M) induced apoptosis in human VSMC from diabetic and nondiabetic patients (NDP), analyzed by DNA fragmentation and by degradation of Bcl-2, in high-glucose-containing medium (15 and 25 mM). This apoptotic effect was inhibited by the activin receptor-like kinase-4/5/7/Smad2 inhibitor 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide (SB-431542), denoting that the TGF-␤1/Smad-2 pathway was involved. Pioglitazone rapidly increased the extracellular TGF-␤1 levels and concomitantly induced phosphorylation of Smad2 in VSMC from DP and NDP. Thus, we demonstrated that pioglitazone induced apoptosis in human VSMC from DP, which are strongly resistant to the induced apoptosis. This effect of pioglitazone might contribute in the treatment of alterations of vascular remodeling in type 2 diabetes mellitus.

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Section: Discussionsupporting

confidence: 67%

Pioglitazone Induces Apoptosis in Human Vascular Smooth Muscle Cells from Diabetic Patients Involving the Transforming Growth Factor-β/Activin Receptor-Like Kinase-4/5/7/Smad2 Signaling Pathway

Ruiz

Redondo

Gordillo‐Moscoso

et al. 2007

J Pharmacol Exp Ther

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“…[75][76][77][78][79] The mechanisms include upregulation of growth arrest and DNA damageinducible gene 45 expression, 75,76 as well as p53 expression (Figure 2). 76 The transforming growth factor ␤1/Smad2 pathway 77,78 and IFN regulatory factor (IRF)-1 79 are also involved ( Figure 2). Pioglitazone increases transforming growth factor ␤1 secretion and phosphorylation of Smad2 in cultured VSMCs.…”

Section: Ppar-␥ Activation/inactivation In Vsmcsmentioning

confidence: 99%

“…77,78 PPAR-␥ agonists increase IRF-1 gene expression while inducing VSMC apoptosis, and conversely inhibition of IRF-1 by antisense oligonucleotide decreases the VSMC apoptosis in vitro. 79 However, VSMC apoptosis can decrease the stability of atherosclerotic plaques and predispose them to rupture. 80 Therefore, the inhibition on the VSMC apoptosis by PPAR-␥ agonists is a double-edged sword.…”

Section: Ppar-␥ Activation/inactivation In Vsmcsmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor-γ–Mediated Effects in the Vasculature

Duan

Usher

Mortensen

2008

Circulation Research

254

205

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Abstract-Peroxisome proliferator-activated receptor (PPAR)-␥ is a nuclear receptor and transcription factor in the steroidsuperfamily. PPAR-␥ agonists, the thiazolidinediones, are clinically used to treat type 2 diabetes. In addition to its function in adipogenesis and increasing insulin sensitivity, PPAR-␥ also plays critical roles in the vasculature. In vascular endothelial cells, PPAR-␥ activation inhibits endothelial inflammation by suppressing inflammatory gene expression and therefore improves endothelial dysfunction. In vascular smooth muscle cells, PPAR-␥ activation inhibits proliferation and migration and promotes apoptosis. In macrophages, PPAR-␥ activation suppresses inflammation by regulating gene expression and increases cholesterol uptake and efflux. A recurring theme in many cell types is the modulation of the innate immunity system particularly through altering the activity of the nuclear factor B. This system is likely to be even more prominent in modulating disease in vascular cells V ascular complications such as atherosclerosis and hypertension are primary causes to mortality associated with diabetes and obesity. With the increasing prevalence of diabetes and obesity, 1,2 vascular protection is critical to decreasing this mortality and improving public health as a whole. To accomplish this protection, one member in the nuclear receptor superfamily, peroxisome proliferator-activated receptor (PPAR)-␥, has emerged as an important player. PPAR-␥ ligands, thiazolidinediones (TZDs), are clinically used for type 2 diabetes. It is clear that improving glucose and lipid homeostasis by treating diabetes or insulin resistance has beneficial effects on cardiovascular diseases.

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“…Evidence exists that oral treatment with PPARg ligands may limit in-stent restenosis in human diabetics [92]. Interestingly, novel data suggest that TZDs impose their effect on SMCs via upregulation of IRF-1 and consecutive activation of p21 cip1 [93]. This particular pathway may also be responsible for the antimigratory effects of TZDs in human SMCs [94].…”

Section: Impact Of Interferon Regulatory Factor-1 (Irf-1) On Vascularmentioning

confidence: 99%

Interference by interferons: Janus faces in vascular proliferative diseases

Wessely

2005

Cardiovascular Research

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Interferons (IFNs) display pleiotropic properties; not only do they protect cells from viral infections but they may also modulate cell growth and differentiation as well as innate and adaptive immune responses. Therapeutic applications of IFNs have proven efficacy in a variety of illnesses, including hepatitis, multiple sclerosis, and some forms of cancer. Emerging evidence has been obtained during recent years that interferons impact on molecular and cellular mechanisms implicated in the development of vascular proliferative diseases such as atherosclerosis, restenosis, and cardiac allograft vasculopathy. Further appreciation and delineation of the precise mechanisms on how interferons influence vascular proliferative disease processes could potentially facilitate the development of novel treatment options attenuating these common causes of cardiovascular morbidity and mortality.

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Interferon Regulatory Factor-1 Mediates PPARγ-Induced Apoptosis in Vascular Smooth Muscle Cells

Cited by 33 publications

References 68 publications

Pioglitazone Induces Apoptosis in Human Vascular Smooth Muscle Cells from Diabetic Patients Involving the Transforming Growth Factor-β/Activin Receptor-Like Kinase-4/5/7/Smad2 Signaling Pathway

Pioglitazone Induces Apoptosis in Human Vascular Smooth Muscle Cells from Diabetic Patients Involving the Transforming Growth Factor-β/Activin Receptor-Like Kinase-4/5/7/Smad2 Signaling Pathway

Peroxisome Proliferator-Activated Receptor-γ–Mediated Effects in the Vasculature

Interference by interferons: Janus faces in vascular proliferative diseases

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