Enhanced Neointima Formation Following Arterial Injury in Immune Deficient Rag-1−/− Mice Is Attenuated by Adoptive Transfer of CD8+ T cells

Dimayuga, Paul C.; Chyu, Kuang‐Yuh; Kirzner, Jonathan; Yano, Juliana; Zhao, Xiaoning; Zhou, Jianchang; Shah, Prediman K.; Cercek, Bojan

doi:10.1371/journal.pone.0020214

Cited by 31 publications

(59 citation statements)

References 40 publications

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“…Increased IP-10 levels have been associated with rapid disease progression in acute HIV-infection 40 and with immunologic treatment failure following ART initiation 41 .…”

Section: Discussionmentioning

confidence: 99%

Rosuvastatin Reduces Vascular Inflammation and T-cell and Monocyte Activation in HIV-Infected Subjects on Antiretroviral Therapy

Funderburg

Jiang

Debanne

et al. 2015

JAIDS Journal of Acquired Immune Deficiency Syndromes

140

121

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Background Despite suppressive antiretroviral therapy (ART), increased levels of immune activation persist in HIV-infected subjects. Statins have anti-inflammatory effects and may reduce immune activation in HIV disease. Methods SATURN-HIV is a randomized, double-blind, placebo-controlled trial assessing the effect of rosuvastatin (10mg/daily) on markers of cardiovascular risk and immune activation in ART-treated patients. T cell activation was measured by expression of CD38, HLA-DR, and PD1. Monocyte activation was measured with soluble markers (sCD14 and sCD163) and by enumeration of monocyte subpopulations and tissue factor (TF) expression. Markers of systemic and vascular inflammation and coagulation were also measured. SATURN-HIV is registered on clinicaltrials.gov, Identifier: NCT01218802 Results Rosuvastatin, compared to placebo, reduced sCD14 (−10.4% vs 0.5%p=0.006), Lp-PLA2 (−12.2% vs −1.7% p=0.0007), and IP-10 (−27.5 vs −8.2%, p=0.03) levels after 48 weeks. The proportion of TF+ patrolling (CD14DimCD16+) monocytes was also reduced by rosuvastatin (−41.6%) compared to the placebo (−18.8%, p=0.005). There was also a greater decrease in the proportions of activated (CD38+HLA-DR+) T cells between the arms (−38.1% vs −17.8%, p=0.009 for CD4+ cells and −44.8% vs −27.4%, p=0.003 for CD8+ cells). Conclusions 48 weeks of rosuvastatin treatment reduced significantly several markers of inflammation and lymphocyte and monocyte activation in ART-treated subjects.

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“…Increased IP-10 levels have been associated with rapid disease progression in acute HIV-infection 40 and with immunologic treatment failure following ART initiation 41 .…”

Section: Discussionmentioning

confidence: 99%

Rosuvastatin Reduces Vascular Inflammation and T-cell and Monocyte Activation in HIV-Infected Subjects on Antiretroviral Therapy

Funderburg

Jiang

Debanne

et al. 2015

JAIDS Journal of Acquired Immune Deficiency Syndromes

140

121

View full text Add to dashboard Cite

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“…Our colocalization studies also identified TUNEL + apoptotic endothelial cells and smooth muscle cells including those in the fibrous cap. CD8 + T lymphocytes are cytolytic to human endothelial cells 5 and smooth muscle cells in injured arteries 6 and also cytotoxic to these cells in vivo. 35 In programmed cell death-1-deficient Ldlr −/− mice, increased CD8 + T cells in the lesions were also associated with more apoptotic cells comprising both smooth muscle cells and nonsmooth muscle.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic and Proinflammatory CD8 ⁺ T Lymphocytes Promote Development of Vulnerable Atherosclerotic Plaques in ApoE-Deficient Mice

et al. 2013

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Background— Heart attacks and strokes, leading causes of deaths globally, arise from thrombotic occlusion of ruptured vulnerable atherosclerotic plaques characterized by abundant apoptosis, large necrotic cores derived from inefficient apoptotic cell clearance, thin fibrous caps, and focal inflammation. The genesis of apoptosis and necrotic cores in these vulnerable atherosclerotic plaques remains unknown. Cytotoxic CD8 + T lymphocytes represent up to 50% of leukocytes in advanced human plaques and dominate early immune responses in mouse lesions, yet their role in atherosclerosis also remains unresolved. Methods and Results— CD8 + T-lymphocyte depletion by CD8α or CD8β monoclonal antibody in apolipoprotein E-deficient mice fed a high-fat diet ameliorated atherosclerosis by reducing lipid and macrophage accumulation, apoptosis, necrotic cores, and monocyte chemoattractant protein 1, interleukin 1β, interferon γ, and vascular cell adhesion molecule 1. Transfer of CD8 + T cells into lymphocyte-deficient, apolipoprotein E-deficient mice partially reconstituted CD8 + T cells in lymphoid compartments and was associated with CD8 + T-cell infiltration in lesions, increased lipid and macrophage accumulation, apoptotic cells, necrotic cores, and interleukin 1β in atherosclerotic lesions. Transfer of CD8 + T cells deficient in perforin, granzyme B, or tumor necrosis factor α but not interferon γ failed to increase atherosclerotic lesions despite partial reconstitution in the lymphoid system and the presence in atherosclerotic lesions. Macrophages, smooth muscle cells, and endothelial cells were identified as apoptotic targets. Conclusions— We conclude that CD8 + T lymphocytes promote the development of vulnerable atherosclerotic plaques by perforin- and granzyme B–mediated apoptosis of macrophages, smooth muscle cells, and endothelial cells that, in turn, leads to necrotic core formation and further augments inflammation by tumor necrosis factor α secretion.

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“…It is possible that this observation is related to the protection of the young vascular wall against chronic inflammation and NIH. Dimayuga et al (6) found that adoptive transfer of CD8 ϩ T cells inhibited neointima formation in mice after arterial injury.…”

Section: Discussionmentioning

confidence: 99%

Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling

Rodriguez-Menocal

Faridi

Martinez

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Padron RI. Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling. Am J Physiol Heart Circ Physiol 306: H641-H653, 2014. First published January 10, 2014; doi:10.1152/ajpheart.00641.2013.-Aging has been associated with pathological vascular remodeling and increased neointimal hyperplasia. The understanding of how aging exacerbates this process is fundamental to prevent cardiovascular complications in the elderly. This study proposes a mechanism by which aging sustains leukocyte adhesion, vascular inflammation, and increased neointimal thickness after injury. The effect of aging on vascular remodeling was assessed in the rat balloon injury model using microarray analysis, immunohistochemistry, and LINCOplex assays. The injured arteries in aging rats developed thicker neointimas than those in younger animals, and this significantly correlated with a higher number of tissue macrophages and increased vascular IL-18. Indeed, IL-18 was 23-fold more abundant in the injured vasculature of aged animals compared with young rats, while circulating levels were similar in both groups of animals. The depletion of macrophages in aged rats with clodronate liposomes ameliorated vascular accumulation of IL-18 and significantly decreased neointimal formation. IL-18 was found to inhibit apoptosis of vascular smooth muscle cells (VSMC) and macrophages, thus favoring both the formation and inflammation of the neointima. In addition, injured arteries of aged rats accumulated 18-fold more fibrinogen-␥ than those of young animals. Incubation of rat peritoneal macrophages with immobilized IL-18 increased leukocyte adhesion to fibrinogen and suggested a proinflammatory positive feedback loop among macrophages, VSMC, and the deposition of fibrinogen during neointimal hyperplasia. In conclusion, our data reveal that concentration changes in vascular cytokine and fibrinogen following injury in aging rats contribute to local inflammation and postinjury neointima formation. inflammation; vascular injury; aging; neointima; vascular smooth muscle cells AGING IS RECOGNIZED AS A MAJOR and independent risk factor for the development of vascular restenosis (29). This risk can be explained by profound, age-dependent changes in vascular structure and physiology that lead to endothelial dysfunction (18) and a chronic inflammatory stage (53), which impair healing and render a vascular system prone to develop occlusive neointimas in response to injury. However, even when this notion is largely accepted, the mechanisms by which aging alters vascular physiology and repair have remained understudied to date.The process of aging increases and sustains inflammation within the vascular wall (52). Macrophages are commonly recognized as the most important cell type in the chronicity of this process (37). Indeed, inflammation in arteries of aged individuals is evidenced by an excessive accumulation of macrophages in the inner layer of the arterial wall (intima), and this occurs in the presence o...

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Enhanced Neointima Formation Following Arterial Injury in Immune Deficient Rag-1−/− Mice Is Attenuated by Adoptive Transfer of CD8+ T cells

Cited by 31 publications

References 40 publications

Rosuvastatin Reduces Vascular Inflammation and T-cell and Monocyte Activation in HIV-Infected Subjects on Antiretroviral Therapy

Rosuvastatin Reduces Vascular Inflammation and T-cell and Monocyte Activation in HIV-Infected Subjects on Antiretroviral Therapy

Cytotoxic and Proinflammatory CD8 ⁺ T Lymphocytes Promote Development of Vulnerable Atherosclerotic Plaques in ApoE-Deficient Mice

Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling

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Enhanced Neointima Formation Following Arterial Injury in Immune Deficient Rag-1−/− Mice Is Attenuated by Adoptive Transfer of CD8+ T cells

Cited by 31 publications

References 40 publications

Rosuvastatin Reduces Vascular Inflammation and T-cell and Monocyte Activation in HIV-Infected Subjects on Antiretroviral Therapy

Rosuvastatin Reduces Vascular Inflammation and T-cell and Monocyte Activation in HIV-Infected Subjects on Antiretroviral Therapy

Cytotoxic and Proinflammatory CD8 + T Lymphocytes Promote Development of Vulnerable Atherosclerotic Plaques in ApoE-Deficient Mice

Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling

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Cytotoxic and Proinflammatory CD8 ⁺ T Lymphocytes Promote Development of Vulnerable Atherosclerotic Plaques in ApoE-Deficient Mice