Platelets and the complement cascade in atherosclerosis

Patzelt, Johannes; Verschoor, Admar; Langer, Harald F.

doi:10.3389/fphys.2015.00049

Cited by 52 publications

(46 citation statements)

References 95 publications

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“…In models of Alzheimer disease, C1q and C3 exert neuroprotective effects via opsonic clearance of amyloid-β aggregates, whereas C1q-mediated complement activation by accumulating amyloid-β fibrils increasingly generate C5-derived effectors that maintain a focal inflammatory state, thus exacerbating disease progression 96,97 . Similar complement-related mechanisms have been described in other neurological and neurodegenerative diseases, as well as in atherosclerosis 96–100 . Another prominent example of a disease of ageing that is mediated by complement is age-related macular degeneration (AMD), a chronic degenerative eye disease, in which complement activation contributes to the geographic atrophy and choroidal neovascularization that causes loss of vision 101 .…”

Section: Complex Involvement In Clinical Disorderssupporting

confidence: 73%

Complement in disease: a defence system turning offensive

2016

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Although the complement system is primarily perceived as a host defence system, a more versatile, yet potentially more harmful side of this innate immune pathway as an inflammatory mediator also exists. The activities that define the ability of the complement system to control microbial threats and eliminate cellular debris — such as sensing molecular danger patterns, generating immediate effectors, and extensively coordinating with other defence pathways — can quickly turn complement from a defence system to an aggressor that drives immune and inflammatory diseases. These host-offensive actions become more pronounced with age and are exacerbated by a variety of genetic factors and autoimmune responses. Complement can also be activated inappropriately, for example in response to biomaterials or transplants. A wealth of research over the past two decades has led to an increasingly finely tuned understanding of complement activation, identified tipping points between physiological and pathological behaviour, and revealed avenues for therapeutic intervention. This Review summarizes our current view of the key activating, regulatory, and effector mechanisms of the complement system, highlighting important crosstalk connections, and, with an emphasis on kidney disease and transplantation, discusses the involvement of complement in clinical conditions and promising therapeutic approaches.

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Section: Complex Involvement In Clinical Disorderssupporting

confidence: 73%

Complement in disease: a defence system turning offensive

2016

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“…Prominent examples of this principle are age-related disorders such as Alzheimer disease, atherosclerosis and AMD 32,33 . In addition, insufficient clearance of apoptotic cells and/or immune complexes owing to deficiencies in early complement components is considered to be a key contributor to autoimmune diseases such as systemic lupus erythematosus (SLE) 19,20 .…”

Section: Indications For Complement Therapiesmentioning

confidence: 99%

The renaissance of complement therapeutics

et al. 2017

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The increasing number of clinical conditions that involve a pathological contribution from the complement system — many of which affect the kidneys — has spurred a regained interest in therapeutic options to modulate this host defence pathway. Molecular insight, technological advances, and the first decade of clinical experience with the complement-specific drug eculizumab, have contributed to a growing confidence in therapeutic complement inhibition. More than 20 candidate drugs that target various stages of the complement cascade are currently being evaluated in clinical trials, and additional agents are in preclinical development. Such diversity is clearly needed in view of the complex and distinct involvement of complement in a wide range of clinical conditions, including rare kidney disorders, transplant rejection and haemodialysis-induced inflammation. The existing drugs cannot be applied to all complement-driven diseases, and each indication has to be assessed individually. Alongside considerations concerning optimal points of intervention and economic factors, patient stratification will become essential to identify the best complement-specific therapy for each individual patient. This Review provides an overview of the therapeutic concepts, targets and candidate drugs, summarizes insights from clinical trials, and reflects on existing challenges for the development of complement therapeutics for kidney diseases and beyond.

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“…Therefore, it is important to consider that peripheral blood cells play an important role in atherogenesis promoting and perpetuating the recruitment of bone marrow monocytes [16–19]. …”

Section: Introductionmentioning

confidence: 99%

Increased ROS production and DNA damage in monocytes are biomarkers of aging and atherosclerosis

et al. 2018

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BackgroundNew evidence demonstrates that aging and dyslipidemia are closely associated with oxidative stress, DNA damage and apoptosis in some cells and extravascular tissues. However, in monocytes, which are naturally involved in progression and/or resolution of plaque in atherosclerosis, this concurrence has not yet been fully investigated. In this study, we evaluated the influence of aging and hypercholesterolemia on serum pro-inflammatory cytokines, oxidative stress, DNA damage and apoptosis in monocytes from apolipoprotein E-deficient (apoE−/−) mice compared with age-matched wild-type C57BL/6 (WT) mice. Experiments were performed in young (2-months) and in old (18-months) male wild-type (WT) and apoE−/− mice.ResultsBesides the expected differences in serum lipid profile and plaque formation, we observed that atherosclerotic mice exhibited a significant increase in monocytosis and in serum levels of pro-inflammatory cytokines compared to WT mice. Moreover, it was observed that the overproduction of ROS, led to an increased DNA fragmentation and, consequently, apoptosis in monocytes from normocholesterolemic old mice, which was aggravated in age-matched atherosclerotic mice.ConclusionsIn this study, we demonstrate that a pro-inflammatory systemic status is associated with an impairment of functionality of monocytes during aging and that these parameters are fundamental extra-arterial contributors to the aggravation of atherosclerosis. The present data open new avenues for the development of future strategies with the purpose of treating atherosclerosis.

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Platelets and the complement cascade in atherosclerosis

Cited by 52 publications

References 95 publications

Complement in disease: a defence system turning offensive

Complement in disease: a defence system turning offensive

The renaissance of complement therapeutics

Increased ROS production and DNA damage in monocytes are biomarkers of aging and atherosclerosis

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