Press Release | Tumor necrosis associate with atherosclerotic lipid accumulation


The article by Dr. Alexander N. Orekhov et al. is published in Current Pharmaceutical Design, 2018

Inflammation is currently a well-documented component of atheroslcerosis pathogenesis, which plays a role at each stage of the disease development. Local activation of endothelial cells causing increase endothelial permeability, infiltration of intima with atherogenic low-density lipoprotein (LDL), and recruitment of circulating immune cells is regarded as a first step of atherosclerotic plaque development. Circulating modified LDL is immunogenic, and forms highly atherogenic aggregates with antibodies that are later accumulated in the arterial wall. In growing plaques, circulating monocytes are attracted to the lesions site by cytokine signalling. In the arterial wall, monocyte-derived macrophages play an active role in lipid accumulation, internalizing large associates of lipoprotein particles by means of phagocytosis. Phagocytic cells with cytoplasm filled by stored lipid droplets called foam cells can be found in developing plaques in large quantities. There is evidence that lipid accumulation in the arterial wall cells in its turn activates cytokine signalling leading to a vicious cycle and further aggravating the disease. However, the immune response in atherosclerosis is not limited to enhanced inflammation, since anti-inflammatory cytokines and alternatively-activated (M2) macrophages are also present in atherosclerotic plaques. Anti-inflammatory M2 macrophages are likely to be responsible for hte resolution of the inflammatory response and tissue remodelling observed in advancing plaques. At later stages of lesion development, lipofibrous plaquest with high lipid contents and cell counts give rise to fibrous plaques that contain less cells and lipids, but more extracellular matrix material.

Although the involvement of cytokines in atherosclerotic lesion development is currently beyond doubt, quantitative evaluation of the expression of pro- and anti-inflammatory cytokines in the plaque remains to be studied in detail. In this study, we analyzed the distribution of two cytokines, pro-inflammatory TNFα and anti-inflammatory CCL18, in sections of human carotid atherosclerotic plaques at different stages of development. Our results demonstrated that both pro- and anti-inflammatory cytokines were present in the plaques, although differently distributed and likely expressed by different cells, and appeared to be enriched as compared to grossly normal intima taken as a control. To test whether the expression of TNFα and CCL18 is increased in atherosclerotic lesions, we performed gene expression analysis by means of quantitative PCR. We found that the expression of both cytokines was indeed increased in different types of atherosclerotic lesions. Moreover, it followed a bell-shaped distribution across the 4 studied plaque stages, gradually increasing from the early initial lesions to fatty streaks, reaching maximum in lipofibrous plaques, and decreasing again in fibrous plaques. This distribution was consistent with our previously published observations of bell-shaped changes of atherosclerotic lesion cellularity, proliferative activity, collagen synthesis and lipid content at different stages of the development. For TNFα, the maximal increase in atherosclerotic lesions reached 2 folds as compared to normal tissue, while for CCL18, this number was 1.5 folds.

We next investigated the relationship between pro- and anti-inflammatory cytokine production and lipid accumulation in cells. To that end, we used cultured human monocyte-derived macrophages with lipid accumulation induced by incubation with atherogenic LDL obtained from atheroslcerosis patients’ blood serum. Non-atherogenic LDL obtained from healthy donors, which did not cause cholesterol accumulation in cultured cells, was used as a control. We found that cholesterol accumulation in macrophages caused by atherogenic LDL treatment was associated with up-regulation of both TNFα and CCL18. The increase in relative gene expression was statistically significant (p=0.05 for TNFα and p=0.023 for CCL18) as compared to non-atherogenic LDL treatment.

In this work, we report the increased expression of pro-inflammatory cytokine TNFα and anti-inflammatory CCL18 in human atherosclerotic lesions, which could be observed microscopically and in gene expression analysis by means of quantitative PCR. Furthermore, we demonstrate that the increase of pro- and anti-inflammatory cytokines expression is associated with cholesterol accumulation caused by atherogenic LDL in cultured cells. It is likely that lipid accumulation is the trigger of cytokine expression in atherosclerotic lesions, since the maximum of expression is observed in atherosclerotic lesions most enriched in lipids. We discuss the implications of these findings for atheroslcerosis pathogenesis, postulating that a splash of cytokine signalling occurs in lesions with the highest lipid contents. We hypothesize that both pro- and anti-inflammatory responses take place in human atherosclerotic lesions, but are probably characterized by different dynamics. While pro-inflammatory signalling occurs rapidly in response to triggering stimuli and is transient, anti-inflammatory response is relatively slow and long-lasting. Under favorable conditions, resolution of inflammation should lead to a healing process and plaque stabilization, while chronic inflammation may aggravate the disease development.

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Press Release | Modified LDL particles activate inflammatory pathways in monocyte-derived macrophages

The article by Dr. . Alexander N. Orekhov et al. is published in Current Pharmaceutical Design, 2018


One of the main characteristics of atherosclerosis is the accumulation of lipids in the intimal layer of the arterial wall. In atherosclerotic plaques, phagocytic cells, such as macrophages, engulf atherogenic low-density lipoprotein (LDL) particles, but are unable to process them, and thus become foam cells, having cytoplasm packed with lipid droplets. Foam cells are characterized by several typical features: they have decreased ability to migrate, while displaying enhanced production of pro-inflammatory cytokines. Therefore foam cells participate in maintaining chronic inflammation in the lesion. Such changes of phenotype in comparison to normal macrophages should be based on changes in gene expression patterns of these cells. The study of foam cell formation is of key importance to our understanding of atherosclerosis pathogenesis and for the development of novel diagnostic and therapeutic tools. However, little is known so far on gene expression changes that take place during conversion of macrophages to foam cells.

Previous studies have shown several clusters of genes up- or down-regulated in macrophages in response to oxidized LDL, which is known to be atherogenic. Among the up-regulated genes were scavenger receptors SCA and CD36, nuclear receptors PPARγ, LXRα and RXRγ, and cholesterol efflux protein ABCA1. Regarding the inflammatory response, modified LDL appeared to trigger up-regulation of genes with anti-inflammatory activities, such as IL1-RA, DSCR1, annexin 1, and the Burton’s tyrosine kinase repressor SH3 protein, and down-regulation of a number of pro-inflammatory genes, including leukotriene A4 hydrolase, cathepsin G, elastase 2, RNase A family 2 and 3 proteins, cytochromeb-245, and CD64. However, modern powerful tools, such as transcriptome analysis, may provide more detailed data on change of gene expression patterns during atherosclerotic plaque development and reveal causative relationships between gene expression patterns and pathologic phenotypic alterations.

We performed a transcriptome analysis of macrophages treated with atherogenic LDL that causes intracellular cholesterol accumulation. We used the strategy of upstream analysis for causal interpretation of the expression changes. This strategy has three major steps: (1) analysis of promoters and enhancers of identified differentially expressed genes to identify transcription factors involved in the process under study; (2) reconstruction of signaling pathways that activate these transcription factors; and (3) identification of master-regulators of these pathways.

In this study, we used human monocyte-derived macrophages treated with different lipoprotein-containing samples : high-density lipoprotein (HDL), native LDL, which does not induce cholesterol accumulation in cultured cells, and 3 types of modified atherogenic LDL (oxidized LDL, acetylated LDL and desialylated LDL). In this experiment, low concentrations of native LDL and HDL did not increase the total or esterified cholesterol content in cultured macrophages. After incubation with the substances, mRNA was isolated from the cells and analysed using high-throughput sequencing on HiSeq 1500.

In this study, we discovered 27 transcription factors, including c-Ets, GR-alpha, BRCA1, E2F-1, E2F-6 and EGR-1, that were potentially responsible for the changes in gene expression induced by modified atherogenic LDL. These transcription factors were used for identifying the master-regulators (genes and proteins) responsible for regulation of large cascades of differentially expressed genes. The most reliable of identified master-regulators were IL7R, TIGIT, CXCL8, F2RL1, EIF2AK3, IL7, TSPYL2, ANXA1, DUSP1 and IL15. In the Discussion section of our paper, we give more detail on each of these master-regulators. In general, the genes that were up-regulated in response to lipid accumulation in macrophages induced by atherogenic LDL were mostly involved in inflammation and immune response, and not in cholesterol metabolism. Our results suggest a possibility that it is not cholesterol accumulation that causes an innate immunity response, but rather the immune response is a consequence of a cellular reaction to modified LDL. These results highlight the importance of the inflammatory component in the pathogenesis of atherosclerosis.

OPEN ACCESS ARTICLE – Pathophysiology of Diabetic Dyslipidaemia

Journal Name: Current Vascular Pharmacology

Author(s): Theodosios Filippatos, Vasilios Tsimihodimos, Eleni Pappa, Moses Elisaf*.




Graphical Abstract:


Background: Patients with diabetes usually exhibit diabetic dyslipidaemia.

Aim: The aim of the review is to present the quantitative and qualitative alterations of lipids and lipoproteins and the associated mechanisms in patients with diabetic dyslipidaemia.

Results: The main quantitative changes observed in patients with diabetic dyslipidaemia are increased triglycerides and decreased high-density lipoprotein (HDL) cholesterol levels. Qualitative abnormalities mainly include increased small dense low-density lipoprotein (LDL) particles (despite similar serum LDL cholesterol levels as non-diabetic subjects) and alterations in the apolipoprotein content of HDL particles. Alterations in the activities of enzymes involved in lipoprotein metabolism, such as cholesteryl ester transfer protein, and the lipoprotein content of lipid particles, along with their glycation and oxidation, play a role in the pathogenesis of diabetic dyslipidaemia.

Conclusion: Diabetic dyslipidaemia is associated with quantitative and qualitative alterations of lipids and lipoproteins, which are associated with increased cardiovascular risk.


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MOST ACCESSED ARTICLE – Potential Role of Endothelin in Early Vascular Aging – Current Hypertension Reviews

Journal: Current Hypertension Reviews

Author(s): Michelle Trindade, Wille Oigman, Mario Fritsch Neves

Graphical Abstract:



Early vascular aging is a process associated with gradual alterations in the vessels, regarding their structure and function, taking a more rapid course than normal biological aging in the arteries. In the presence of cardiovascular disease, these age-associated alterations are accelerated, contributing in the appearance or the progression of cardiovascular disease, such as high blood pressure, dyslipidemia, smoking and diabetes. Endothelin-1 (ET-1) is the most abundant and important endothelin produced by vascular cells. ET-1 exerts its biological actions through the activation of two receptors: ETA and ETB. Many important functions are mediated by the activation of these receptors, such as cardiovascular remodeling, vasoconstriction, cell proliferation and differentiation, production of extracellular matrix, and water and sodium secretion control. ETA receptor seems to participate in the pathogenesis and development of diseases, such as diabetes, atherosclerosis, systemic and pulmonary hypertension, and cardiac remodeling after myocardial ischemia, whereas ETB receptor seems to prevent the overstimulation of ETA receptor, acting as a clearance receptor. Increased ET-1 system activity may contribute to vascular dysfunction in aging via multiple pathways, such as direct hemodynamic effects, vascular oxidative stress, inflammatory activity, mitogenic stimulation of the vascular smooth muscle cells and fibrotic processes. Endothelin receptor antagonists were considered to be used for the treatment of some diseases like hypertension, diabetes and chronic kidney disease. However, besides pulmonary hypertension, this class is not in clinical use because of the side effects and the availability of safer drugs for the treatment of these diseases.

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Contributed Article: “The Role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Cardiovascular Homeostasis: A Non-Systematic Literature Review



Essa Hariri

Contributed Article: “The Role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Cardiovascular Homeostasis: A Non-Systematic Literature Review


Dima A. Sabbah

Contributed Article: “The Role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Cardiovascular Homeostasis: A Non-Systematic Literature Review

Brand New Issue: Inflammation & Allergy-Drug Targets

  • Inflammaging in Skin and Other Tissues – The Roles of Complement System and Macrophage
Author(s): Yong Zhuang and John Lyga
Pages 153-161 (9)

Inflammaging refers to a continuous, low-grade inflammation associated with aging. Such chronic inflammatory response could build up with time and gradually causes tissue damage. It is considered as one of the driving forces for many age-related diseases such as diabetes, atherosclerosis, age-related macular degeneration (AMD), and skin aging. There is mounting evidence that indicates aging is driven by the pro-inflammatory cytokines and substances produced by our body’s innate immune system. The macrophage and complement system, two important components of innate immune system, have attracted more and more attention since they appear to be involved in the pathogenesis of several inflammaging-associated diseases, such as AMD and atherosclerosis. This paper will review what we know about these two innate immune systems in the pathogenesis of AMD, atherosclerosis and skin aging.

Avon Global R&D, 1 Avon Place, Suffern, NY, 10901, USA.
  • Acne Vulgaris: an Inflammatory Disease Even Before the Onset of Clinical Lesions
Author(s): Marco Alexandre Rocha, Caroline Sousa Costa and Edileia Bagatin
Pages 162-167 (6)

Acne is a chronic self-limited disease, which affects mostly teenagers, without gender difference. In recent years, the incidence has increased in female adults. The factors involved in this epidemiological observation are still under discussion in the literature.Clinically, acne is characterized by different types of lesions. The disease affects the regions rich in sebaceous glands (face, chest and upper back). The clinical lesions are: open and closed comedones, erythematous papules, pustules, nodules and different types of scars. Taking into consideration the general concept of inflammation (redness, pain, heat and loss of function), acne is traditionally classified as non-inflammatory (open and closed comedones) and inflammatory (other primary lesions). With the knowledge advancement this concept seems to be wrong and therefore acne would be an inflammatory disease even before the onset of their clinical lesions.


Escola Paulista de Medicina — Universidade Federal de Sao Paulo (EPM-Unifesp), Brazil.
  • Effect of Botanicals on Inflammation and Skin Aging: Analyzing the Evidence
Author(s): Amanda Suggs, Patricia Oyetakin-White and Elma D. Baron
Pages 168-176 (9)

The skin and its immune system manifest a decline in physiologic function as it undergoes aging. External insults such as ultraviolet light exposure cause inflammation, which may enhance skin aging even further leading to cancer and signs of photoaging. There is a potential role for botanicals as an adjunct modality in the prevention of skin aging. Numerous over-the-counter anti-aging products are commercially available, many of which boast unverified claims to reduce stress, inflammation and correct signs of aging. In this article we reviewed the scientific literature for data on frequently published “anti-inflammaging” additives such as vitamins A, C and E and green tea. We also analyzed the evidence available on five promising ingredients commonly found in anti-aging products, namely, argan oil, rosemary, pomegranate, Coenzyme Q10, and Coffeeberry. Though there may be an increasing amount of scientific data on a few of these novel botanicals, in general, there remains a lack of clinical data to support the anti-aging claims made.

Department of Dermatology, University Hospitals Case Medical Center 11100 Euclid Avenue, Lakeside 3500, Mailstop 5028, Cleveland, OH 44106-5028, USA.
  • Brain-Skin Connection: Stress, Inflammation and Skin Aging
Author(s): Ying Chen and John Lyga
Pages 177-190 (14)

The intricate relationship between stress and skin conditions has been documented since ancient times. Recent clinical observations also link psychological stress to the onset or aggravation of multiple skin diseases. However, the exact underlying mechanisms have only been studied and partially revealed in the past 20 years or so. In this review, the authors will discuss the recent discoveries in the field of “Brain-Skin Connection”, summarizing findings from the overlapping fields of psychology, endocrinology, skin neurobiology, skin inflammation, immunology, and pharmacology.

Global R&D, Avon Products. 1 Avon Place, Suffern, NY 10901, USA.
  • Biological Treatments for SAPHO Syndrome: An Update
Author(s): Davide Firinu, Giuseppe Murgia, Maria Maddalena Lorrai, Maria Pina Barca, Maria Monica Peralta, Paolo Emilio Manconi and Stefano R. del Giacco
Pages 199-205 (7)

Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis (SAPHO) syndrome is a rare and often unrecognized disease with prominent inflammatory cutaneous and articular manifestations. Since the identification of the syndrome many immunosuppressive drugs have been used for the management of SAPHO, with variable results. The use of anti- TNF-α agents as a therapeutic option for SAPHO cases unresponsive or refractory to conventional drugs, demonstrated their efficacy for bone, skin and joints manifestations. TNF-α is a pro-inflammatory cytokine and pivotal regulator of other cytokines, including IL-1 β , IL-6 and IL-8, involved in inflammation, acute-phase response induction and chemotaxis. IL-1 inhibition strategies with Anakinra have proven their efficacy as first and second line treatment. We herein review the literature concerning the use of biological drugs in patients with SAPHO syndrome. In addition, we describe for the first time the use of Ustekinumab, an antibody against the p40 subunit of IL-12 and IL-23, after failure of multiple drugs including anti-TNF-α and Anakinra. This anti-IL12/IL23 agent could be a promising therapeutic option, also considering the opportunity to interfere with the IL23/TH17 pathway, which we recently found disturbed. Furthermore, a rationale emerges for the use of the new anti-IL-1 antagonists or the IL-17 blockade, in particular for the most difficult-to-treat SAPHO cases.

Department of Medical Sciences “M. Aresu”, Unit of Internal Medicine, Allergy and Clinical Immunology, University of Cagliari, Azienda Ospedaliero Universitaria, SS 554-Bivio Sestu, I-09042 Monserrato (CA), Italy.
  • Cardiac and Muscular Involvement in Idiopathic Inflammatory Myopathies: Noninvasive Diagnostic Assessment and the Role of Cardiovascular and Skeletal Magnetic Resonance Imaging
Author(s): Sophie Mavrogeni, Petros P. Sfikakis, Theodoros Dimitroulas, Genovefa Kolovou and George D. Kitas
Pages 206-216 (11)

Idiopathic inflammatory myopathies (IIMs) are rare autoimmune diseases and include dermatomyositis, polymyositis, necrotizing myopathy and inclusion body myositis; they are characterized by inflammation of skeletal muscle and other internal organs and may potentially lead to irreversible damage and death. Only a small percentage of IIM has clinically overt cardiac disease; however, heart involvement is one of the leading causes of death and therefore, early detection remains a challenge.Biochemical markers and non-invasive methods such as the electrocardiogram and echocardiography have a role in diagnosis, but lack sensitivity in identifying patients with early, sublinical cardiac abnormalities. Endomyocardial and skeletal muscle biopsies are very useful, but invasive techniques and cannot be used for routine follow-up. Cardiac and skeletal magnetic resonance imaging, due to their capability to perform tissue characterization, has emerged as novel techniques for the early detection and follow-up of myocardial and skeletal muscle tissue changes (oedema, inflammation, fibrosis) in IIM. However, the clinical implications of using these approaches and their cost /benefit ratio require further evaluation.


Onassis Cardiac Surgery Center, 50 Esperou Street, 175-61 P.Faliro, Athens, Greece.
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