Amelioration of Human Allograft Arterial Injury by Atorvastatin or Simvastatin Correlates With Reduction of Interferon-γ Production by Infiltrating T Cells

Yi, Tai; Rao, Deepak A.; Tang, Paul C.; Wang, Yinong; Cuchara, Lisa; Bothwell, Alfred L.M.; Colangelo, Christopher M.; Tellides, George; Pober, Jordan S.; Lorber, Marc I.

doi:10.1097/tp.0b013e318183eefa

Cited by 18 publications

(12 citation statements)

References 27 publications

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“…Previous studies indicated that T‐cells‐derived IFN‐γ is responsible for increased proliferation of VSMCs in transplanted arteries [Wang et al, ; Yu et al, ]. Similarly, in animal models of vascular wound repair, genetic ablation or pharmacological blockade of IFN‐γ leads to decreased inflammatory response and impaired VSMC proliferation, accompanying with attenuated neointimal formation [Yi et al, ; Hirata et al, ]. In this study, we now additionally show that IFN‐γ signaling is critically involved in modulating VSMC phenotypic switch from the contractile state to the synthetic state, which is indicated by reduced expression of SMC‐specific markers including SM22α and calponin.…”

Section: Discussionsupporting

confidence: 73%

High Mobility Group Box 1 Mediates Interferon-γ-Induced Phenotypic Modulation of Vascular Smooth Muscle Cells

Wang

et al. 2016

J. Cell. Biochem.

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The phenotypic modulation of VSMCs is a key cellular event driving neointimal formation and vascular remodeling. As a multifaceted cytokine of cell-mediated immunity, IFN-γ has been shown to play a critical role in the pathogenesis of vascular proliferative diseases. Although the important function of IFN-γ on regulating VSMC activation is well established, the molecular mechanisms by which elicits VSMC responses are poorly defined. Recent studies have identified HMGB1 as a principal effector to mediate IFN-γ-dependent biological functions in multiple cell types. Moreover, SIRT1 has emerged as a critical regulator of cellular processes through deacetylating multiple substrates, including HMGB1. Thus, we examined the role of IFN-γ on HMGB1 release, SIRT1 expression, and VSMC phenotypic modulation as well as the underlying molecular mechanisms. We show that IFN-γ dose-dependently induces HMGB1 cytoplasmic accumulation and its active release from VSMCs, resulting in enhanced HMGB1 in the medium. Conversely, IFN-γ treatment led to a dramatic decrease in SIRT1 expression. Additionally, pretreatment with resveratrol, a selective SIRT1 activator, abrogated IFN-γ-induced HMGB1 translocation and its release. Moreover, IFN-γ stimulates VSMC phenotypic modulation to an activated synthetic state characterized by the repression of SMC differentiation markers such as SM22α and calponin and the increase in cell motility. In contrast, blocking HMGB1 release or activity by resveratrol and HMGB1-neutralizing antibody prevents IFN-γ-induced phenotypic modulation of VSMCs. Overall, this study provides the first evidence showing that HMGB1 plays a critical role in regulating VSMC phenotypic modulation, suggesting that HMGB1 may be a potential therapeutic target to prevent vascular occlusive diseases. J. Cell. Biochem. 118: 518-529, 2017. © 2016 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 73%

High Mobility Group Box 1 Mediates Interferon-γ-Induced Phenotypic Modulation of Vascular Smooth Muscle Cells

Wang

et al. 2016

J. Cell. Biochem.

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“…Our findings suggest that PPAR γ agonists have the capacity to suppress memory alloreactive T cells responsible for vascular graft rejection via a PPAR γ -dependent mechanism. Interestingly, in the present study, we show complete prevention of neointima formation by pioglitazone; in our previous study testing the effects of statins, 48 we reported a reduction in but not complete inhibition of T cell–driven arterial remodeling. The PPAR γ agonists are approved for treatment of type 2 diabetes mellitus.…”

Section: Discussionsupporting

confidence: 53%

Peroxisome Proliferator–Activated Receptor-γ Agonists Prevent In Vivo Remodeling of Human Artery Induced by Alloreactive T Cells

Tobiásová

Zhang

et al. 2011

Circulation

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Background Ligands activating the transcription factor peroxisome proliferator–activated receptor-γ (PPARγ) have antiinflammatory effects. Vascular rejection induced by allogeneic T cells can be responsible for acute and chronic graft loss. Studies in rodents suggest that PPARγ agonists may inhibit graft vascular rejection, but human T-cell responses to allogeneic vascular cells differ from those in rodents, and the effects of PPARγ in human transplantation are unknown. Methods and Results We tested the effects of PPARγ agonists on human vascular graft rejection using a model in which human artery is interposed into the abdominal aorta of immunodeficient mice, followed by adoptive transfer of allogeneic (to the artery donor) human peripheral blood mononuclear cells. Interferon-γ–dependent rejection ensues within 4 weeks, characterized by intimal thickening, T-cell infiltrates, and vascular cell activation, a response resembling clinical intimal arteritis. The PPARγ agonists 15-deoxy-prostaglandin-J2, ciglitazone, and pioglitazone reduced intimal expansion, intimal infiltration of CD45RO+ memory T cells, and plasma levels of inflammatory cytokines. The PPARγ antagonist GW9662 reversed the protective effects of PPARγ agonists, confirming the involvement of PPARγ-mediated pathways. In vitro, pioglitazone inhibited both alloantigen-induced proliferation and superantigen-induced transendothelial migration of memory T cells, indicating the potential mechanisms of PPARγ effects. Conclusion Our results suggest that PPARγ agonists inhibit allogeneic human memory T cell responses and may be useful for the treatment of vascular graft rejection.

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“…In an in vivo model of graft arterial disease, statins were shown to decrease IFN-γ expression by T cells within the grafts (37). The ability of statins to reduce IFNG expression in each of 4 human T cell preparations was suppressed when KLF2 upregulation was blocked, establishing a causal link between the statin effects on T cell function and on KLF2 upregulation.…”

Section: Figurementioning

confidence: 97%

Statin-induced Kruppel-like factor 2 expression in human and mouse T cells reduces inflammatory and pathogenic responses

Bu¹,

Tarrio²,

Grabie³

et al. 2010

J. Clin. Invest.

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The transcription factor kruppel-like factor 2 (KLF2) is required for the quiescent and migratory properties of naive T cells. Statins, a class of HMG-CoA reductase inhibitors, display pleiotropic immunomodulatory effects that are independent of their lipid-lowering capacity and may be beneficial as therapeutic agents for T cell-mediated inflammatory diseases. Statins upregulate KLF2 expression in endothelial cells, and this activity is associated with an antiinflammatory phenotype. We therefore hypothesized that the immunomodulatory effects of statins are due, in part, to their direct effects on T cell KLF2 gene expression. Here we report that lipophilic statin treatment of mouse and human T cells increased expression of KLF2 through a HMG-CoA/ prenylation-dependent pathway. Statins also diminished T cell proliferation and IFN-γ expression. shRNA blockade of KLF2 expression in human T cells increased IFN-γ expression and prevented statin-induced IFN-γ reduction. In a mouse model of myocarditis induced by heart antigen-specific CD8 + T cells, both statin treatment of the T cells and retrovirally mediated overexpression of KLF2 in the T cells had similar ameliorating effects on disease induction. We conclude that statins reduce inflammatory functions and pathogenic activity of T cells through KLF2-dependent mechanisms, and this pathway may be a potential therapeutic target for cardiovascular diseases.

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Amelioration of Human Allograft Arterial Injury by Atorvastatin or Simvastatin Correlates With Reduction of Interferon-γ Production by Infiltrating T Cells

Cited by 18 publications

References 27 publications

High Mobility Group Box 1 Mediates Interferon-γ-Induced Phenotypic Modulation of Vascular Smooth Muscle Cells

High Mobility Group Box 1 Mediates Interferon-γ-Induced Phenotypic Modulation of Vascular Smooth Muscle Cells

Peroxisome Proliferator–Activated Receptor-γ Agonists Prevent In Vivo Remodeling of Human Artery Induced by Alloreactive T Cells

Statin-induced Kruppel-like factor 2 expression in human and mouse T cells reduces inflammatory and pathogenic responses

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