Inflammation and Immunity in Diseases of the Arterial Tree

Libby, Peter; Hansson, Göran K.

doi:10.1161/circresaha.116.301313

Cited by 326 publications

(276 citation statements)

References 23 publications

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“…On the contrary, transition to pathological intimal thickening, the earliest form of progressive atherosclerosis, is characterized by accumulation of ApoB100 within the medial wall, which, in fact, is much earlier than previously reported 29. Demonstration that the transition to irreversible atherosclerosis is associated with a loss of internal elastic lamina integrity hallmarks the beginning of medial and adventitial involvement in atherosclerosis, a phenomenon that warrants further investigation 30, 31…”

Section: Discussionmentioning

confidence: 84%

Systematic Evaluation of the Cellular Innate Immune Response During the Process of Human Atherosclerosis

Dijk

Rijs

Wezel

et al. 2016

JAHA

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BackgroundThe concept of innate immunity is well recognized within the spectrum of atherosclerosis, which is primarily dictated by macrophages. Although current insights to this process are largely based on murine models, there are fundamental differences in the atherosclerotic microenvironment and associated inflammatory response relative to humans. In this light, we characterized the cellular aspects of innate immune response in normal, nonprogressive, and progressive human atherosclerotic plaques.Methods and ResultsA systematic analysis of innate immune response was performed on 110 well‐characterized human perirenal aortic plaques with immunostaining for specific macrophage subtypes (M1 and M2 lineage) and their activation markers, neopterin and human leukocyte antigen–antigen D related (HLA‐DR), together with dendritic cells (DCs), natural killer (NK) cells, mast cells, neutrophils, and eosinophils. Normal aortae were devoid of low‐density lipoprotein, macrophages, DCs, NK cells, mast cells, eosinophils, and neutrophils. Early, atherosclerotic lesions exhibited heterogeneous populations of (CD68+) macrophages, whereby 25% were double positive “M1” (CD68+/ inducible nitric oxide synthase [iNOS]+/CD163−), 13% “M2” double positive (CD68+/iNOS −/CD163+), and 17% triple positive for (M1) iNOS (M2)/CD163 and CD68, with the remaining (≈40%) only stained for CD68. Progressive fibroatheromatous lesions, including vulnerable plaques, showed increasing numbers of NK cells and fascin‐positive cells mainly localized to the media and adventitia whereas the M1/M2 ratio and level of macrophage activation (HLA‐DR and neopterin) remained unchanged. On the contrary, stabilized (fibrotic) plaques showed a marked reduction in macrophages and cell activation with a concomitant decrease in NK cells, DCs, and neutrophils.ConclusionsMacrophage “M1” and “M2” subsets, together with fascin‐positive DCs, are strongly associated with progressive and vulnerable atherosclerotic disease of human aorta. The observations here support a more complex theory of macrophage heterogeneity than the existing paradigm predicated on murine data and further indicate the involvement of (poorly defined) macrophage subtypes or greater dynamic range of macrophage plasticity than previously considered.

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Section: Discussionmentioning

confidence: 84%

Systematic Evaluation of the Cellular Innate Immune Response During the Process of Human Atherosclerosis

Dijk

Rijs

Wezel

et al. 2016

JAHA

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“…6 Anemia may be associated with elevated levels of inflammatory mediators, 7 and inflammation is associated with atherosclerotic progression. 8 As such, anemia could theoretically contribute to progression of coronary artery disease. However, coexisting conditions (cardiovascular and other) are also intricately related to both inflammation and hemoglobin levels and it remains uncertain as to whether anemia is causally implicated in adverse outcomes or whether it is a marker of other, or advanced, disease.…”

Section: Introductionmentioning

confidence: 99%

Hemoglobin and Change in Hemoglobin Status Predict Mortality, Cardiovascular Events, and Bleeding in Stable Coronary Artery Disease

Kalra

Greenlaw

Ferrari

et al. 2017

The American Journal of Medicine

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“…Atherosclerosis, as a chronic inflammatory disease,30, 31, 32, 33 plays a major role in the pathogenesis of cardiovascular diseases 34. Therapeutic targeting of different inflammatory pathways might be effective in preventing and treating cardiovascular diseases 35, 36, 37.…”

Section: Discussionmentioning

confidence: 99%

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Yang

Liu

et al. 2017

JAHA

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BackgroundKruppel‐like factor 2 (KLF2) is an important zinc‐finger transcription factor that maintains endothelial homeostasis by its anti‐inflammatory, ‐thrombotic, ‐oxidative, and ‐proliferative effects in endothelial cells. In light of the potent vasoprotective effects of KLF2, modulating KLF2 expression or function could give rise to new therapeutic strategies to treat cardiovascular diseases.Methods and ResultsHigh‐throughput drug screening based on KLF2 promoter luciferase reporter assay was performed to screen KLF2 activators. Real‐time PCR and western blot were used to detect gene and protein expression. Identified KLF2 activator was orally administered to ApoE−/− mice to evaluate anti‐atherosclerotic efficacy. By screening 2400 compounds in the Spectrum library, we identified suberanilohydroxamic (SAHA) acid, also known as vorinostat as a pharmacological KLF2 activator through myocyte enhancer factor 2. We found that SAHA exhibited anti‐inflammatory effects and attenuated monocyte adhesion to endothelial cells inflamed with tumor necrosis factor alpha. We further showed that the inhibitory effect of SAHA on endothelial inflammation and ensuing monocyte adhesion was KLF2 dependent using KLF2‐deficient mouse lung endothelial cells or KLF2 small interfering RNA– depleted human endothelial cells. Importantly, we observed that oral administration of SAHA reduced diet‐induced atherosclerotic lesion development in ApoE−/− mice without significant effect on serum lipid levels.ConclusionsThese results demonstrate that SAHA has KLF2‐dependent anti‐inflammatory effects in endothelial cells and provide the proof of concept that KLF2 activation could be a promising therapeutic strategy for treating atherosclerosis.

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Inflammation and Immunity in Diseases of the Arterial Tree

Cited by 326 publications

References 23 publications

Systematic Evaluation of the Cellular Innate Immune Response During the Process of Human Atherosclerosis

Systematic Evaluation of the Cellular Innate Immune Response During the Process of Human Atherosclerosis

Hemoglobin and Change in Hemoglobin Status Predict Mortality, Cardiovascular Events, and Bleeding in Stable Coronary Artery Disease

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

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