Atherogenesis and the humoral immune response to modified lipoproteins

Virella, Gabriel; Lopes‐Virella, Maria F.

doi:10.1016/j.atherosclerosis.2008.03.025

Cited by 60 publications

(54 citation statements)

References 98 publications

(140 reference statements)

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“…6 oxLDL-specific T lymphocytes are present in the vessel wall where they are locally restimulated and further stimulate macrophages by cytokine release. 7,8 Furthermore, oxLDL is cytotoxic and damages the endothelium, 9 thereby favoring platelet adhesion. 10 In advanced atherosclerotic lesions, the cytotoxicity of oxLDL may even result in irreversible cell necrosis.…”

Section: Methods and Resultsmentioning

confidence: 99%

Effect of the oxLDL Binding Protein Fc-CD68 on Plaque Extension and Vulnerability in Atherosclerosis

Zeibig

Wagner

et al. 2011

Circulation Research

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Rationale: There is strong evidence that oxidative modification of low-density lipoprotein (oxLDL) plays a critical role in atherogenesis and that oxLDL may profoundly influence the mechanical stability of atherosclerotic plaques.Objective: To block oxLDL, we designed, expressed, and tested Fc-CD68, a soluble oxLDL binding protein consisting of human Fc and the extracellular domain of the human oxLDL-binding receptor CD68. Methods and Results:Fc-CD68 bound with high specific affinity to oxLDL and strongly bound and colocalized with oxLDL in plaques. To study the effects of repeated administrations of Fc-CD68 on the progression of atherosclerosis and plaque vulnerability, 12-and 16-week old cholesterol-fed ApoE ؊/؊ mice received either Fc-CD68 (n‫)6؍‬ or Fc control protein (n‫6؍‬ to 8) thrice weekly for 4 weeks. Macroscopic and histological analysis of Sudan red lipid staining showed strong and significant reduction of plaque extension in the aorta and in the aortic root, respectively. Histological analysis of pentachrome-and Sirius-stained sections of the brachiocephalic arteries of 20 week-old ApoE ؊/؊ mice revealed that Fc-CD68 significantly reduced the occurrence of spontaneous ruptures of established plaques by Ϸ20%, compared with Fc and drastically increased the collagen content of plaques. Furthermore, in immunostained sections of the brachiocephalic artery and the aortic root, Fc-CD68 reduced the infiltration of plaques with T lymphocytes, and macrophages by Ϸ50% and 30%, respectively. Key Words: oxLDL Ⅲ atherosclerosis Ⅲ Fc-CD68 Ⅲ soluble oxLDL binding protein O xidatively modified low-density lipoprotein (oxLDL) plays a critical role in atherogenesis and contributes to the progression of atherosclerosis in various ways. 1,2 It can induce the transformation of macrophages into lipid-laden foam cells, 3,4 it is a chemotactic agent for monocytes, and it reduces the motility of macrophages which then become resident in the arterial intima. 5 In addition, oxLDL is recognized as foreign by the immune system. 6 oxLDL-specific T lymphocytes are present in the vessel wall where they are locally restimulated and further stimulate macrophages by cytokine release. 7,8 Furthermore, oxLDL is cytotoxic and damages the endothelium, 9 thereby favoring platelet adhesion. 10 In advanced atherosclerotic lesions, the cytotoxicity of oxLDL may even result in irreversible cell necrosis. 10,11 In addition to contributing to atherosclerosis, oxLDL may profoundly influence the mechanical stability of atherosclerotic plaques, because foam cells offer little mechanical stability and because activated macrophages may secrete factors that weaken plaques, ie, metalloproteinases. 12,13 Rupture of atherosclerotic plaques leads to vascular injury and subsequent myocardial infarction and stroke. Several studies have demonstrated conclusively that the morphology of the atherosclerotic plaques, rather than their size, is predictive for the frequency of plaque ruptures (summarized by Rekhter 14 ). The most relevant morphological characteris...

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Section: Methods and Resultsmentioning

confidence: 99%

Effect of the oxLDL Binding Protein Fc-CD68 on Plaque Extension and Vulnerability in Atherosclerosis

Zeibig

Wagner

et al. 2011

Circulation Research

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“…16 The importance of immune activation during atherogenesis is a rising concept in the last years, and evidence suggests that LDL-containing ICs are involved in this process. 9,10 Furthermore, increased Fc␥R expression has been found in plaques and leukocytes from atherosclerotic patients, 38 and Fc␥R deficiency protects against atherosclerosis in mice. 11 Our study demonstrates that SOCS represses IC-induced STAT activation, and extends the concept that SOCS have more diverse functions than simply acting as negative regulators of cytokine receptor signaling in vascular cells.…”

Section: Discussionmentioning

confidence: 99%

“…9 Elevated levels of LDL-containing immune complexes (ICs) and their IgG Fc receptors (Fc␥R) have been found in atherosclerotic patients. 10 Furthermore, Fc␥R mediates the clearance of ICs containing LDL and foam cell formation, 10 and Fc␥R activation in vascular cells is critical for atherosclerosis development in mice. 11 The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is an essential intracellular mechanism of cytokines and other stimuli that regulates gene expression and cellular activation, proliferation, and differentiation.…”

mentioning

confidence: 99%

Suppressors of Cytokine Signaling Modulate JAK/STAT-Mediated Cell Responses During Atherosclerosis

Ortiz-Muñoz

Martin-Ventura

Hernández-Vargas

et al. 2009

ATVB

118

130

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Objective-Suppressors of cytokine signaling (SOCS) proteins are intracellular regulators of receptor signal transduction, mainly Janus kinase/signal transducers and activators of transcription (JAK/STAT). We investigated the effects of SOCS modulation on the JAK/STAT-dependent responses in vascular cells, and their implication in atherosclerotic plaque development. Methods and Results-Immunohistochemistry in human plaques revealed a high expression of SOCS1 and SOCS3 by vascular smooth muscle cells (VSMCs) and macrophages in the inflammatory region of the shoulders, when compared to the fibrous area. SOCS were also increased in aortic lesions from apoE Ϫ/Ϫ mice. In cultured VSMCs, endothelial cells, and monocytes, SOCS1 and SOCS3 were transiently induced by proinflammatory cytokines, proatherogenic lipoproteins, and immune molecules. Furthermore, overexpression of SOCS suppressed STAT activation and reduced inflammatory gene expression and cell growth, whereas SOCS knockdown increased these cell responses. In vivo, antisense oligodeoxynucleotides targeting SOCS3 exacerbated the atherosclerotic process in apoE Ϫ/Ϫ mice by increasing the size, leukocyte content, and chemokine expression in the lesions. Key Words: atherosclerosis Ⅲ inflammation Ⅲ signal transduction Ⅲ proliferation Ⅲ chemokines A therosclerosis is a chronic inflammatory disease that involves a complex interaction of the artery wall and its cellular components, lipoproteins, and circulating blood elements. 1 Leukocyte invasion and vascular smooth muscle cell (VSMC) proliferation are key early events in lesion development. 2 Low-density lipoproteins (LDL) and cytokines, such as interferon ␥ (IFN␥) and interleukin-6 (IL-6), influence the dynamics of vascular cell function and are main mediators of inflammation during atherogenesis. 2,3 Native and modified forms of LDL induce a variety of biological properties, including cytokine expression, changes in monocyte/macrophages motility and arterial vasomotricity, and VSMC mitogenesis. 4,5 IFN␥ is expressed in human and experimental plaques, and induces the expression of major histocompatibility complex-II, downregulates scavenger receptors, and modulates vascular cell proliferation. 2,6 IL-6 is secreted from endothelial cells (ECs), VSMCs, and leukocytes, and has multiple biological activities, including lymphocyte activation, acute-phase proteins induction, and proliferation. 7,8 Evidence supports the involvement of cellular and humoral immune responses in atherosclerosis, from its initiation to its thrombotic complication. 9 Elevated levels of LDL-containing immune complexes (ICs) and their IgG Fc receptors (Fc␥R) have been found in atherosclerotic patients. 10 Furthermore, Fc␥R mediates the clearance of ICs containing LDL and foam cell formation, 10 and Fc␥R activation in vascular cells is critical for atherosclerosis development in mice. 11 The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is an essential intracellular mechanism of cytokines and other stimuli tha...

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“…10 Low-density lipoprotein transforms to oxidized low-density lipoprotein with infection 11 and promotes activation of macrophage and T lymphocytes, resulting in the formation of foam cells. 4,5 Elevated C-reactive protein is associated with inflammatory processes and atherosclerosis. 9,10 In addition, C-reactive protein binds to oxidized low-density lipoprotein, thereby further increasing the possibility of atherosclerosis developing.…”

Section: Discussionmentioning

confidence: 99%

“…1 Atherosclerosis increases cardiovascular morbidity and mortality and has been associated with various infectious or inflammatory diseases. 2,3 A variety of mechanisms, such as immune reaction, endothelial dysfunction, or oxidized lowdensity lipoprotein, [3][4][5] may cause atherosclerosis. The aim of this study was to estimate the risk of stroke among patients with PID during a 3-year follow-up period after diagnosis and to compare the results with those of a cohort of control patients.…”

mentioning

confidence: 99%

Association Between Stroke and Patients With Pelvic Inflammatory Disease

Chen

Tseng

Hsieh

et al. 2011

Stroke

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Background and Purpose-The aim of this study is to estimate the risk of stroke in a 3-year period after pelvic inflammatory disease (PID) using a nationwide population-based study. Methods-Our study cohort consisted of all patients with a diagnosis of PID (Nϭ64 515) between 2004 and 2005 with a control cohort (1:2) of age-matched controls (Nϭ129 030). Each patient was tracked from hospitalization until the end of 2006. Cox regressions were performed to compute the 3-year stroke-free survival rates after adjusting for possible confounding factors. Results-We found that women with PID were more likely to have strokes than the control population. After adjusting for potential confounding factors, the adjusted hazard ratio of stroke was 1.63 (95% CI, 1.45-1.85) for PID patients as compared to the general population cohort. Sensitivity analysis using a bootstrap approach further ensured the validity of the results of our study. Conclusions-We

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Atherogenesis and the humoral immune response to modified lipoproteins

Cited by 60 publications

References 98 publications

Effect of the oxLDL Binding Protein Fc-CD68 on Plaque Extension and Vulnerability in Atherosclerosis

Effect of the oxLDL Binding Protein Fc-CD68 on Plaque Extension and Vulnerability in Atherosclerosis

Suppressors of Cytokine Signaling Modulate JAK/STAT-Mediated Cell Responses During Atherosclerosis

Association Between Stroke and Patients With Pelvic Inflammatory Disease

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