Proteasome-Mediated Reduction in Proapoptotic Molecule Bim Renders CD4
            <sup>+</sup>
            CD28
            <sup>null</sup>
            T Cells Resistant to Apoptosis in Acute Coronary Syndrome

Kovalcsik, Edit; Antunes, Ricardo Filipe da Silva; Baruah, Paramita; Kaski, Juan Carlos; Dumitriu, Ingrid E.

doi:10.1161/circulationaha.114.013710

Cited by 43 publications

(46 citation statements)

References 42 publications

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“…These cells express multiple cytotoxins including granzymes A and B, perforin and granulysin as well as pro‐inflammatory cytokines IFN‐γ and TNF‐α (Teo et al, ). They are highly resistant to apoptosis (Kovalcsik et al, ) and appear to accumulate in vulnerable coronary atherosclerotic plaques (Nakajima et al, ). Activation appears to be triggered by heat shock protein 60 antigens (Zal et al, ; Zal et al, ) and by the co‐stimulatory molecules Ox40 (CD134) and 41BB (CD137) present on CD4 + CD28−T cells in acute coronary syndromes (Dumitriu et al, ).…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic lymphocytes and atherosclerosis: significance, mechanisms and therapeutic challenges

Kyaw

Peter

et al. 2017

British J Pharmacology

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Cytotoxic lymphocytes encompass natural killer lymphocytes (cells) and cytotoxic T cells that include CD8+ T cells, natural killer (NK) T cells, γ, δ (γδ)-T cells and human CD4 + CD28À T cells.These cells play critical roles in inflammatory diseases and in controlling cancers and infections. Cytotoxic lymphocytes can be activated via a number of mechanisms that may involve dendritic cells, macrophages, cytokines or surface proteins on stressed cells. Upon activation, they secrete pro-inflammatory cytokines as well as anti-inflammatory cytokines, chemokines and cytotoxins to promote inflammation and the development of atherosclerotic lesions including vulnerable lesions, which are strongly implicated in myocardial infarctions and strokes. Here, we review the mechanisms that activate and regulate cytotoxic lymphocyte activity, including activating and inhibitory receptors, cytokines, chemokine receptors-chemokine systems utilized to home to inflamed lesions and cytotoxins and cytokines through which they affect other cells within lesions. We also examine their roles in human and mouse models of atherosclerosis and the mechanisms by which they exert their pathogenic effects. Finally, we discuss strategies for therapeutically targeting these cells to prevent the development of atherosclerotic lesions and vulnerable plaques and the challenge of developing highly targeted therapies that only minimally affect the body's immune system, avoiding the complications, such as increased susceptibility to infections, which are currently associated with many immunotherapies for autoimmune diseases. LINKED ARTICLESThis article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/ 10.1111/bcp.v82.4/issuetoc Abbreviation TCR, T cell receptor; MHC, major histocompablity complex; NKG2D, natural-killer group 2, member D; TRAIL, TNF-related apoptosis-inducing ligand; DNAM-1, DNAX accessory molecule-1; Clec9A, C-type lectin domain family 9 member A

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Section: Introductionmentioning

confidence: 99%

Cytotoxic lymphocytes and atherosclerosis: significance, mechanisms and therapeutic challenges

Kyaw

Peter

et al. 2017

British J Pharmacology

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“…In addition, CD41CD28 null T cells are less sensitive to glucocorticoid-mediated suppression (19). Such reduced sensitivity to glucocorticoids could be due to expression of antiapoptotic molecules (20,21), alternative signaling pathways and costimulatory receptors (22,23), and/or lower expression of glucocorticoid receptors (24). The potential contribution of CD28 null T cells to muscle damage in polymyositis is still unknown, although we have previously demonstrated that the infiltrating T cells in affected muscle of polymyositis patients are predominantly CD81CD28 null and CD41CD28 null T cells (7).…”

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confidence: 99%

CD4+ and CD8+ CD28^null T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis

Pandya

Venalis

Al-Khalili

et al. 2016

Arthritis & Rheumatology

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Objective. Inflammatory T cell infiltrates in the skeletal muscle tissue of patients with polymyositis are dominated by CD28-negative effector (CD28 null ) T cells of both the CD4 and CD8 lineage. These cells are potentially cytotoxic, and the aim of the present study was to develop a fully autologous cell culture system in which to investigate the functional contribution of such CD28 null T cells to myotoxicity.Methods. In vitro cocultures of autologous skeletal muscle cells and T cell subsets obtained from 5 polymyositis patients were performed. Myotoxicity of T cells was quantified by calcein release and flow cytometric analyses. T cell degranulation was blocked with concanamycin A. Specific blocking of perforin, cytokines, and HLA was performed using antibodies.Results. Both CD41CD28 null and CD81CD28 null T cells induced more muscle cell death than did their CD281 counterparts. Differentiated muscle cells (myotubes) were more sensitive to T cell-mediated cell death than were their precursors (myoblasts). Both CD81 and CD41 CD28 null T cells displayed perforin polarization toward muscle cells and secreted higher levels of granzyme B and interferon-g (IFNg) in coculture than did CD281 T cells. The myotoxic effects of CD28 null T cells were reduced upon the blocking of perforin, cytokines, and HLA. Addition of IFNg or tumor necrosis factor did not induce skeletal muscle cell death in the absence of T cells; however, it did up-regulate HLA expression on muscle cells.Conclusion. Myotoxicity of CD41 and CD81 CD28 null T cells is mediated by directed perforindependent killing and can be further influenced by IFNg-induced HLA expression on muscle cells. The data suggest that CD28 null T cells are key effector cells that contribute to the muscle cell damage in polymyositis.

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“…A growing body of evidence has implicated UPS in neointimal formation . Recent studies have identified increased activity of ubiquitination–proteasome in neointimal areas and furthermore, inhibition of UPS by MG132 effectively reduced neointima formation in vivo, which corresponds to strong antiproliferative effects in vitro and in vivo, suggesting the UPS as a new target in the prevention of vascular restenosis . However, the specific protein targets of UPS remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Cavin‐1 Expression via Increasing Caveolin‐1 Degradation Prompts the Proliferation and Migration of Vascular Smooth Muscle Cells in Balloon Injury–Induced Neointimal Hyperplasia

Zhou

Chen

Liu

et al. 2017

JAHA

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BackgroundPercutaneous coronary intervention has been widely used in the treatment of ischemic heart disease, but vascular restenosis is a main limitation of percutaneous coronary intervention. Our previous work reported that caveolin‐1 had a key functional role in intimal hyperplasia, whereas whether Cavin‐1 (another important caveolae‐related protein) was involved is still unknown. Therefore, we will investigate the effect of Cavin‐1 on neointimal formation.Methods and ResultsBalloon injury markedly reduced Cavin‐1 protein and enhanced ubiquitin protein expression accompanied with neointimal hyperplasia in injured carotid arteries, whereas Cavin‐1 mRNA had no change. In cultured vascular smooth muscle cells (VSMCs), Cavin‐1 was downregulated after inhibition of protein synthesis by cycloheximide, which was distinctly prevented by pretreatment with proteasome inhibitor MG132 but not by lysosomal inhibitor chloroquine, suggesting that proteasomal degradation resulted in Cavin‐1 downregulation. Knockdown of Cavin‐1 by local injection of Cavin‐1 short hairpin RNA (shRNA) into balloon‐injured carotid arteries in vivo promoted neointimal formation. In addition, inhibition or overexpression of Cavin‐1 in cultured VSMCs in vitro prompted or suppressed VSMC proliferation and migration via increasing or decreasing extracellular signal‐regulated kinase phosphorylation and matrix‐degrading metalloproteinases‐9 activity, respectively. However, under basic conditions, the effect of Cavin‐1 on VSMC migration was stronger than on proliferation. Moreover, our results indicated that Cavin‐1 regulated caveolin‐1 expression via lysosomal degradation pathway.ConclusionsOur study revealed the role and the mechanisms of Cavin‐1 downregulation in neointimal formation by promoting VSMC proliferation, migration, and synchronously enhancing caveolin‐1 lysosomal degradation. Cavin‐1 may be a potential therapeutic target for the treatment of postinjury vascular remodeling.

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Proteasome-Mediated Reduction in Proapoptotic Molecule Bim Renders CD4 ⁺ CD28 ^null T Cells Resistant to Apoptosis in Acute Coronary Syndrome

Cited by 43 publications

References 42 publications

Cytotoxic lymphocytes and atherosclerosis: significance, mechanisms and therapeutic challenges

Cytotoxic lymphocytes and atherosclerosis: significance, mechanisms and therapeutic challenges

CD4+ and CD8+ CD28^null T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis

Downregulation of Cavin‐1 Expression via Increasing Caveolin‐1 Degradation Prompts the Proliferation and Migration of Vascular Smooth Muscle Cells in Balloon Injury–Induced Neointimal Hyperplasia

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Proteasome-Mediated Reduction in Proapoptotic Molecule Bim Renders CD4 + CD28 null T Cells Resistant to Apoptosis in Acute Coronary Syndrome

Cited by 43 publications

References 42 publications

Cytotoxic lymphocytes and atherosclerosis: significance, mechanisms and therapeutic challenges

Cytotoxic lymphocytes and atherosclerosis: significance, mechanisms and therapeutic challenges

CD4+ and CD8+ CD28null T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis

Downregulation of Cavin‐1 Expression via Increasing Caveolin‐1 Degradation Prompts the Proliferation and Migration of Vascular Smooth Muscle Cells in Balloon Injury–Induced Neointimal Hyperplasia

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Proteasome-Mediated Reduction in Proapoptotic Molecule Bim Renders CD4 ⁺ CD28 ^null T Cells Resistant to Apoptosis in Acute Coronary Syndrome

CD4+ and CD8+ CD28^null T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis