Protective Role of CXC Receptor 4/CXC Ligand 12 Unveils the Importance of Neutrophils in Atherosclerosis

Zernecke, Alma; Bot, Ilze; Djalali-Talab, Yassin; Shagdarsuren, Erdenechimeg; Bidzhekov, Kiril; Meiler, Svenja; Krohn, Regina M.; Schober, Andreas; Sperandio, Markus; Soehnlein, Oliver; Bornemann, Jörg; Tacke, Frank; Biessen, Erik A.L.; Weber, Christian

doi:10.1161/circresaha.107.160697

Cited by 363 publications

(325 citation statements)

References 53 publications

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“…In the early stages of atherosclerosis the neutrophil plays a key role, through the release of specific chemoattractant mediators, in the consequent recruitment of inflammatory monocytes to the athero-prone site (44,63). Using an acute model of inflammation, we have shown that treatment of ApoE KO mice with inorganic nitrate reduces first neutrophil recruitment, followed by consequent reductions in the number of inflammatory monocytes.…”

Section: (B) the Same Pattern Was Observed In Erythrocytes (G And H)mentioning

confidence: 94%

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

Khambata

Ghosh

Rathod

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Reduced bioavailable nitric oxide (NO) plays a key role in the enhanced leukocyte recruitment reflective of systemic inflammation thought to precede and underlie atherosclerotic plaque formation and instability. Recent evidence demonstrates that inorganic nitrate (NO 3 − ) through sequential chemical reduction in vivo provides a source of NO that exerts beneficial effects upon the cardiovascular system, including reductions in inflammatory responses. We tested whether the antiinflammatory effects of inorganic nitrate might prove useful in ameliorating atherosclerotic disease in Apolipoprotein (Apo)E knockout (KO) mice. We show that dietary nitrate treatment, although having no effect upon total plaque area, caused a reduction in macrophage accumulation and an elevation in smooth muscle accumulation within atherosclerotic plaques of ApoE KO mice, suggesting plaque stabilization. We also show that in nitratefed mice there is reduced systemic leukocyte rolling and adherence, circulating neutrophil numbers, neutrophil CD11b expression, and myeloperoxidase activity compared with wild-type littermates. Moreover, we show in both the ApoE KO mice and using an acute model of inflammation that this effect upon neutrophils results in consequent reductions in inflammatory monocyte expression that is associated with elevations of the antiinflammatory cytokine interleukin (IL)-10. In summary, we demonstrate that inorganic nitrate suppresses acute and chronic inflammation by targeting neutrophil recruitment and that this effect, at least in part, results in consequent reductions in the inflammatory status of atheromatous plaque, and suggest that this effect may have clinical utility in the prophylaxis of inflammatory atherosclerotic disease.

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Section: (B) the Same Pattern Was Observed In Erythrocytes (G And H)mentioning

confidence: 94%

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

Khambata

Ghosh

Rathod

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Although the pathophysiological significance of these cells during atherogenesis has not yet been well documented, it is suggested that these cells are pro-atherogenic [73]. Neutrophils play a major role in the development of many forms of vasculitis [74,75].…”

Section: Pathophysiology Of Accelerated Atherosclerosis In Vasculitismentioning

confidence: 99%

Translational Mini-Review Series on Immunology of Vascular Disease: Accelerated atherosclerosis in vasculitis

Tervaert

2009

Clinical and Experimental Immunology

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SummaryPremature atherosclerosis has been observed during the course of different systemic inflammatory diseases such as rheumatoid arthritis and sytemic lupus erythematosus. Remarkably, relatively few studies have been published on the occurrence of accelerated atherosclerosis in patients with vasculitis. In giant cell arteritis (GCA), mortality because of ischaemic heart disease is not increased. In addition, intima media thickness (IMT) is lower in patients with GCA than in age-matched controls. In contrast, IMT is increased significantly in Takayasu arteritis, another form of large vessel vasculitis occurring in younger patients. In Takayasu arteritis and in Kawasaki disease, a form of medium-sized vessel vasculitis, accelerated atherosclerosis has been well documented. In small vessel vasculitis because of anti-neutrophil cytoplasmic autoantibodies-associated vasculitis, cardiovascular diseases are a major cause of mortality. IMT measurements reveal conflicting results. During active disease these patients experience acceleration of the atherosclerotic process. However, when inflammation is controlled, these patients have atherosclerotic development as in healthy subjects. Several risk factors, such as diabetes and hypertension, are present more often in patients with vasculitis compared with healthy controls. In addition, steroids may be pro-atherogenic. Most importantly, many patients have impaired renal function, persistent proteinuria and increased levels of C-reactive protein, well-known risk factors for acceleration of atherosclerosis. Enhanced oxidation processes, persistently activated T cells and reduced numbers of regulatory T cells are among the many pathophysiological factors that play a role during acceleration of atherogenesis. Finally, autoantibodies that may be relevant for acceleration of atherosclerosis are found frequently in elevated titres in patients with vasculitis. Because patients have an increased risk for cardiovascular events, vasculitis should be treated with as much care as possible. In addition, treatment should be considered with angiotensin-converting-enzyme inhibitors and/or angiotensin receptor-1 blockers, statins and acetylsalicyl acid. Finally, classical risk factors for cardiovascular disease should be monitored and treated as much as possible.

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“…Our data suggest that higher logSDF-1α levels and lower CXCR4 expression in PBMCs are accompanied by higher leukocyte, neutrophil, and lymphocyte counts in PB from male and female BHLP patients. However, lower logSDF-1α levels are accompanied by lower leukocyte and neutrophil counts in PB in male HLP patients (Zernecke et al 2008). Other investigators have reported that TNF-1α activation results in leukocyte recruitment and may explain the leukocytosis observed in patients with hypercholesterolemia (Han et al 1999;Steinberg 2002;Bobryshev 2006).…”

Section: Discussionmentioning

confidence: 95%

“…Moreover, in patients with either stable or unstable angina, there was decreased surface expression, but increased gene expression, in peripheral blood mononuclear cells (PBMCs) of the SDF-1α receptor CXCR4. SDF-1α may, therefore, exert a protective effect against atherogenesis (Damås et al 2002;Zernecke et al 2008).…”

mentioning

confidence: 99%

Stromal Cell-Derived Factor-1α as a Novel Biomarker for Hyperlipidemia

Lin

Zhang

et al. 2012

Tohoku J. Exp. Med.

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Stromal cell-derived factor-1 (SDF-1) is expressed in a wide variety of organs, such as heart, and plays a pivotal role in the mobilization of hematopoietic stem and progenitor cells in bone marrow. SDF-1α, a common subtype of SDF-1, may control hematopoiesis and angiogenesis, but its role in the pathogenesis of hyperlipidemia is unknown. The aim of this study was to determine the role of SDF-1α in the pathogenesis of hyperlipidemia. First, log-transformed SDF-1α serum levels (logSDF-1α) were significantly higher in male patients with borderline high lipid profile (BHLP; n = 28; 2.15 ± 0.08 ng/ml) compared to control subjects (n = 37; 1.94 ± 0.06 ng/ml; P < 0.01). The logSDF-1α in male patients with high lipid profile (HLP; n = 33; 1.95 ± 0.08 ng/ml) were lower than BHLP patients (P < 0.01). The logSDF-1α was positively associated with HDL-C only in female patients (n = 125; r = 0.379, P = 0.016). These results suggest the different pathophysiology in male and female patients with hyperlipidemia. Moreover, flow cytometry analysis showed that expression of the SDF-1α receptor, CXC-chemokine receptor 4, was lower in peripheral blood mononuclear cells of patients with BHLP (n = 10) and HLP (n = 10), compared to control subjects (n = 10; P < 0.001). Lastly, peripheral blood leukocyte, neutrophil and lymphocyte counts were higher in BHLP patients (n = 62; P < 0.05). Taken together, we suggest SDF-1α as a biomarker of hyperlipidemia that may be helpful to uncover the pathogenesis of hyperlipidemia.

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Protective Role of CXC Receptor 4/CXC Ligand 12 Unveils the Importance of Neutrophils in Atherosclerosis

Cited by 363 publications

References 53 publications

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

Translational Mini-Review Series on Immunology of Vascular Disease: Accelerated atherosclerosis in vasculitis

Stromal Cell-Derived Factor-1α as a Novel Biomarker for Hyperlipidemia

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