Myocardin regulates vascular smooth muscle cell inflammatory activation and disease.

OBJECTIVE: Atherosclerosis, the cause of 50% of deaths in westernized societies, is widely regarded as a chronic vascular inflammatory disease. Vascular smooth muscle cell (VSMC) inflammatory activation in response to local proinflammatory stimuli contributes to disease progression and is a pervasive feature in developing atherosclerotic plaques. Therefore, it is of considerable therapeutic importance to identify mechanisms that regulate the VSMC inflammatory response. APPROACH AND RESULTS: We report that myocardin, a powerful myogenic transcriptional coactivator, negatively regulates VSMC inflammatory activation and vascular disease. Myocardin levels are reduced during atherosclerosis, in association with phenotypic switching of smooth muscle cells. Myocardin deficiency accelerates atherogenesis in hypercholesterolemic apolipoprotein E(-/-) mice. Conversely, increased myocardin expression potently abrogates the induction of an array of inflammatory cytokines, chemokines, and adhesion molecules in VSMCs. Expression of myocardin in VSMCs reduces lipid uptake, macrophage interaction, chemotaxis, and macrophage-endothelial tethering in vitro, and attenuates monocyte accumulation within developing lesions in vivo. These results demonstrate that endogenous levels of myocardin are a critical regulator of vessel inflammation. CONCLUSIONS: We propose myocardin as a guardian of the contractile, noninflammatory VSMC phenotype, with loss of myocardin representing a critical permissive step in the process of phenotypic transition and inflammatory activation, at the onset of vascular disease.This work was supported by Wellcome Trust funding for MAJ (Studentship 086799/Z/08/Z), British Heart Foundation grants (PG/10/007/28184) for AT, and (RG/08/009/25841) for MRB, and SS (FS/13/29/30024), the Cambridge NIHR Biomedical Research Centre and the NIH for JM (NIH HL-117907).This is the accepted manuscript of a paper published in Arteriosclerosis, Thrombosis, and Vascular Biology, 2015, doi: 10.1161/ATVBAHA.114.30521

Leukocyte Bim deficiency does not impact atherogenesis in ldlr -/- mice, despite a pronounced induction of autoimmune inflammation

Proapoptotic Bcl-2 family member Bim is particularly relevant for deletion of autoreactive and activated T and B cells, implicating Bim in autoimmunity. As atherosclerosis is a chronic inflammatory process with features of autoimmune disease, we investigated the impact of hematopoietic Bim deficiency on plaque formation and parameters of plaque stability. Bim−/− or wild type bone marrow transplanted ldlr−/− mice were fed a Western type diet (WTD) for 5 or 10 weeks, after which they were immunophenotyped and atherosclerotic lesions were analyzed. Bim−/− transplanted mice displayed splenomegaly and overt lymphocytosis. CD4+ and CD8+ T cells were more activated (increased CD69 and CD71 expression, increased interferon gamma production). B cells were elevated by 147%, with a shift towards the pro-atherogenic IgG-producing B2 cell phenotype, resulting in a doubling of anti-oxLDL IgG1 antibody titers in serum of bim−/− mice. Bim−/− mice displayed massive intraplaque accumulation of Ig complexes and of lesional T cells, although this did not translate in changes in plaque size or stability features (apoptotic cell and macrophage content). The surprising lack in plaque phenotype despite the profound pro-atherogenic immune effects may be attributable to the sharp reduction of serum cholesterol levels in WTD fed bim−/− mice

Uremia does not affect neointima formation in mice

Atherosclerotic cardiovascular disease is a major complication of chronic kidney disease (CKD). CKD leads to uremia, which modulates the phenotype of aortic smooth muscle cells (SMCs). Phenotypic modulation of SMCs plays a key role in accelerating atherosclerosis. We investigated the hypothesis that uremia potentiates neointima formation in response to vascular injury in mice. Carotid wire injury was performed on C57BL/6 wt and apolipoprotein E knockout (Apoe−/−) mice two weeks after induction of uremia by 5/6 nephrectomy. Wire injury led to neointima formation and downregulation of genes encoding classical SMC markers (i.e., myocardin, α-smooth muscle actin, SM22-alpha, and smooth muscle myosin heavy chain) in both wt and Apoe−/− mice. Contrary to our expectations, uremia did not potentiate neointima formation, nor did it affect intimal lesion composition as judged from magnetic resonance imaging and histological analyses. Also, there was no effect of uremia on SMC marker gene expression in the injured carotid arteries, suggesting that there may be different effects of uremia on SMCs in different vascular beds. In conclusion, uremia does not accelerate neointima formation in response to wire injury of the carotid artery in mice.</p

Mast Cells in Cardiovascular Disease: From Bench to Bedside

Mast cells are pluripotent leukocytes that reside in the mucosa and connective tissue. Recent studies show an increased prevalence of cardiovascular disease among patients with mastocytosis, which is a hematological disease that is characterized by the accumulation of mast cells due to clonal proliferation. This association suggests an important role for mast cells in cardiovascular disease. Indeed, the evidence establishing the contribution of mast cells to the development and progression of atherosclerosis is continually increasing. Mast cells may contribute to plaque formation by stimulating the formation of foam cells and causing a pro-inflammatory micro-environment. In addition, these cells are able to promote plaque instability by neo-vessel formation and also by inducing intraplaque hemorrhage. Furthermore, mast cells appear to stimulate the formation of fibrosis after a cardiac infarction. In this review, the available data on the role of mast cells in cardiovascular disease are summarized, containing both in vitro research and animal studies, followed by a discussion of human data on the association between cardiovascular morbidity and diseases in which mast cells are important: Kounis syndrome, mastocytosis and allergy

Разработка аппаратно-программного комплекса для УЗ томографии на основе С – развертки

Статья посвящена УЗ томографии, которая является передовым, активно развивающимся методом визуализации внутренней структуры материалов и изделий. Одним из направлений УЗ томографии является визуализация, реализованная на основе С – сканирования.The article is devoted to ultrasonic tomography, which is an advanced, actively developing method for visualizing the internal structure of materials and products. One of the directions of ultrasonic tomography is visualization, realized on the basis of C - scan

Increased Plasma IgE Accelerate Atherosclerosis in Secreted IgM Deficiency.

RATIONALE: Deficiency of secreted IgM (sIgM-/-) accelerates atherosclerosis in Ldlr-/-mice. Several atheroprotective effects of increased levels of IgM antibodies have been suggested, including preventing inflammation induced by oxidized low-density lipoprotein and promoting apoptotic cell clearance. However, the mechanisms by which the lack of sIgM promotes lesion formation remain unknown. OBJECTIVE: To identify the mechanisms by which sIgM deficiency accelerates atherosclerosis in mice. METHODS AND RESULTS: We here show that both sIgM-/- and Ldlr-/-sIgM-/- mice develop increased plasma IgE titers because of impaired generation of B cells expressing the low-affinity IgE receptor CD23, which mediates the clearance of IgE antibodies. We further report that Ldlr-/-sIgM-/- mice exhibit increased numbers of activated mast cells and neutrophils in the perivascular area of atherosclerotic plaques. Treatment with an anti-IgE-neutralizing antibody fully reversed vascular inflammation and accelerated atherosclerotic lesion formation in cholesterol-fed Ldlr-/-sIgM-/- mice. CONCLUSIONS: Thus, our data identify a previously unsuspected mechanism by which sIgM deficiency aggravates atherosclerosis

NLRP3 Inflammasome inhibition by the novel bispecific antibody InflamAb attenuates atherosclerosis in apolipoprotein E-deficient mice

Background: Cardiovascular disease remains the most common cause of mortality worldwide, which is attributable to the underlying chronic inflammatory condition atherosclerosis. The NLRP3 inflammasome contributes to this inflammatory process in atherosclerosis by producing IL-1β. Components of the intracellular NLRP3 inflammasome have been shown to be expressed by macrophages in the atherosclerotic plaque and are a potential target for intervention. Objectives: Here, we aimed to determine the efficacy of the novel bispecific antibody InflamAb, designed to target the interleukin-1 receptor type 1 and the NLRP3 inflammasome, in inhibiting atherosclerosis. Methods: We established the efficacy of InflamAb to inhibit IL-1β production upon NLRP3 inflammasome activation in bone marrow derived macrophages and in Western-type diet fed Apoe-/- mice. Subsequently, we treated Apoe-/- mice with developing collar-induced atherosclerosis and Apoe-/- mice with established atherosclerotic plaques with InflamAb.Results: InflamAb inhibited IL-1β secretion from bone marrow derived macrophages and circulating IL-1β levels in vivo, upon NLRP3 inflammasome activation. Furthermore, InflamAb treatment significantly inhibited atherosclerotic plaque development, which was accompanied by a reduction in relative macrophage and necrotic core content. Established atherosclerotic lesion size in the aortic root was not affected by InflamAb treatment, however, InflamAb significantly reduced relative macrophage and necrotic core content in these plaques.Conclusions: In conclusion, inhibition of the NLRP3 inflammasome by the bispecific antibody InflamAb shows promising efficacy in inhibiting atherosclerotic plaque development and destabilization in mice.<br/

Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis

The TGF-β family member GDF-15 promotes lesion formation and plaque instability in atherosclerosis-prone LDLr-deficient mice