Danger Signaling in Atherosclerosis

Zimmer, Sebastian; Grebe, Alena; Latz, Eicke

doi:10.1161/circresaha.116.301135

Cited by 86 publications

(56 citation statements)

References 233 publications

(224 reference statements)

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“…Although specific ligands for most PRR have been identified, numerous PRRs are not restricted to a single exogenous danger signal but rather show cross reactivity to several endogenous molecules such as IFNs, heat shock proteins or oxidized cholesterol 4, 27. One may speculate that nucleic acids from apoptotic or necrotic vascular cells could stimulate RLRs of neighbouring cell and provoke a pro‐inflammatory vascular state that serves as a fertile ground to accelerate vascular inflammation in viral infections.…”

Section: Discussionmentioning

confidence: 99%

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MDA‐5 activation by cytoplasmic double‐stranded RNA impairs endothelial function and aggravates atherosclerosis

Asdonk

Steinmetz

Krogmann

et al. 2016

J Cellular Molecular Medi

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Recent studies have highlighted the relevance of viral nucleic acid immunorecognition by pattern recognition receptors in atherogenesis. Melanoma differentiation associated gene 5 (MDA‐5) belongs to the intracellular retinoic acid inducible gene‐I like receptors and its activation promotes pro‐inflammatory mechanisms. Here, we studied the effect of MDA‐5 stimulation in vascular biology. To gain insights into MDA‐5 dependent effects on endothelial function, cultured human coronary artery endothelial cells (HCAEC) were transfected with the synthetic MDA‐5 agonist polyIC (long double‐stranded RNA). Human coronary endothelial cell expressed MDA‐5 and reacted with receptor up‐regulation upon stimulation. Reactive oxygen species formation, apoptosis and the release of pro‐inflammatory cytokines was enhanced, whereas migration was significantly reduced in response to MDA‐5 stimulation. To test these effects in vivo, wild‐type mice were transfected with 32.5 μg polyIC/JetPEI or polyA/JetPEI as control every other day for 7 days. In polyIC‐treated wild‐type mice, endothelium‐dependent vasodilation and re‐endothelialization was significantly impaired, vascular oxidative stress significantly increased and circulating endothelial microparticles and circulating endothelial progenitor cells significantly elevated compared to controls. Importantly, these effects could be abrogated by MDA‐5 deficiency in vivo. Finally, chronic MDA‐5 stimulation in Apolipoprotein E/toll‐like receptor 3 (TLR3) double‐deficient (ApoE−/−/TLR3−/−) mice‐enhanced atherosclerotic plaque formation. This study demonstrates that MDA‐5 stimulation leads to endothelial dysfunction, and has the potential to aggravate atherosclerotic plaque burden in murine atherosclerosis. Thus, the spectrum of relevant innate immune receptors in vascular diseases and atherogenesis might not be restricted to TLRs but also encompasses the group of RLRs including MDA‐5.

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Section: Discussionmentioning

confidence: 99%

“…Specific classes and motifs of these nucleic acids bind and activate so called pattern recognition receptors (PRRs) and in turn mediate the production of pro‐inflammatory cytokines and growth factors attributed to atherosclerotic plaque formation 4.…”

Section: Introductionmentioning

confidence: 99%

MDA‐5 activation by cytoplasmic double‐stranded RNA impairs endothelial function and aggravates atherosclerosis

Asdonk

Steinmetz

Krogmann

et al. 2016

J Cellular Molecular Medi

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“…Most studies of arterial microbiology have been devoted to the role of bacterial factors in the pathogenesis of atherosclerosis. The atherogenic process resembles many aspects of chronic infl ammation [7][8][9][10][11][12][13], a response that may be promoted by microorganisms [14][15][16][17][18]. The presumptive role of microorganisms in the development of atherosclerosis was revisited in several reviews.…”

Section: Introductionmentioning

confidence: 99%

Bacteria of leg atheromatous arteries responsible for inflammation

Rutkowska

Mościcka-Wesołowska

et al. 2016

Vasa

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Summary:Background: Ischaemia of the lower limbs is frequently followed by infl ammation and, in advanced cases, necrosis of peripheral tissues. Whether this is caused by arterial hypoperfusion only or by the presence of bacteria in the arterial walI as well remains unclear. The aim of the study was to prove the presence and source of bacteria in arterial specimens and evaluate their chemotactic properties resulting in the formation of periarterial cellular infi ltrates. Materials and methods: Bacterial culture and testing for 16sRNA were performed in fragments of popliteal artery harvested from amputated limbs. Carotid artery plaques served as controls. Fragments of arteries were transplanted into scid mice to evaluate their chemotactic activity for macrophages. Results: a) higher prevalence of isolates and 16sRNA in atherosclerotic popliteal than carotid arteries, b) high density of plaque and periarterial infi ltrates and mRNA level for pro-infl ammatory cytokines in popliteal arteries, c) prevalent microbes were Staphylococcus aureus, S. epidermidis and Enterococci, d) foot skin and arterial bacterial phenotypes and DNA revealed evident similarities, and e) more intensive mouse macrophage accumulation in popliteal than carotid implants into scid mice. Conclusions: The presence of bacteria in the lower limb arterial wall was documented. They may predispose to infl ammation secondary to ischaemic changes.

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“…Это провоспалительный цитокин, ответственный за многие клинические проявления воспалительных заболеваний. Особенностью ИЛ 1␤ является то, что он, в отличие от большинства других цитокинов, синте-зируется в неактивной форме и для своей активации требует участия внутриклеточного супрамолекулярного комплекса -инфламмасомы, которая участвует в пре-вращении неактивного про-ИЛ 1␤ в активную моле-кулу, индуцируя, таким образом, процесс воспаления [11][12][13]. С учением об инфламмасоме связаны достиже-ния в плане изучения фундаментальных основ развития аутовоспалительных заболеваний.…”

Section: Introductionunclassified

“…Все пациенты с сЮА на момент начала тера-пии канакинумабом получали метотрексат в дозе 12 (11,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) мг/м 2 поверхности тела, опыт применения других базисных противовоспалительных препаратов имели в анамнезе 4 пациента (2 получали циклофос-фан, 2 -циклоспорин). Все получали нестероидные противовоспалительные средства и глюкокортикоиды в дозе 0,33 (0,15-0,42) мг/кг в сутки (по преднизолону).…”

Section: Introductionunclassified