Chronic unilateral arm lymphedema correlates with increased intima-media thickness in the brachial artery

Summary: Drainage of the arterial wall via adventitial lymphatic vessels has been shown to play a pivotal role for vessel wall homeostasis. Also, retrograde cholesterol transport is ensured via this route, but no studies exist to demonstrate that lymphatic stasis would represent a mechanism to initiate atherosclerotic lesion formation in human arteries. To test this hypothesis, we embarked on a simple clinical experiment, assessing wall thickness in limb arteries with lymphedema after surgical intervention, with the contralateral limb serving as control. Using ultrasound imaging, the differential thickness was assessed separately for the three arterial wall layers. The potential of disease progression by lymphostasis was addressed by depiction of longitudinal results according to the time after lymph dissection.

Long Non-coding RNA MIAT Controls Advanced Atherosclerotic Lesion Formation and Plaque Destabilization

Background: Long noncoding RNAs (lncRNAs) are important regulators of biological processes involved in vascular tissue homeostasis and disease development. The current study assessed the functional contribution of the lncRNA Myocardial Infarction Associated Transcript ( MIAT ) to atherosclerosis and carotid artery disease. Methods: We profiled differences in RNA transcript expression in patients with advanced carotid artery atherosclerotic lesions from the Biobank of Karolinska Endarterectomies (BiKE). The lncRNA MIAT was identified as the most upregulated non-coding RNA transcript in carotid plaques compared to non-atherosclerotic control arteries, which was confirmed by quantitative real time PCR (qRT-PCR) and in situ hybridization. Results: Experimental knockdown of MIAT , utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) not only markedly decreased proliferation and migration rates of cultured human carotid artery smooth muscle cells (SMCs), but also increased their apoptosis. Mechanistically, MIAT regulated SMC proliferation via the EGR1-ELK1-ERK pathway. MIAT is further involved in SMC phenotypic transition to proinflammatory macrophage-like cells through binding to the promoter region of KLF4 and enhancing its transcription. Studies using Miat −/− and Miat −/− ApoE −/− mice as well as Yucatan LDLR −/− mini-pigs confirmed the regulatory role of this lncRNA in SMC de- and trans-differentiation and advanced atherosclerotic lesion formation. Conclusions: The lncRNA MIAT is a novel regulator of cellular processes in advanced atherosclerosis that controls proliferation, apoptosis, and phenotypic transition of SMCs as well as the pro-inflammatory properties of macrophages.

Atherosclerosis: Causes and Cures

Atherosclerosis is a systemic disease that occurs due to the formation of Fibro-fatty lesions in arteries that block blood flow. The process of Atherosclerosis is initiated through mechanical, chemical, and immunological activation of the endothelium. Even there are microorganisms involved in the different stages of atherosclerosis. There are a number of molecular factors, RNA’s, macrophages and enzymes that play a vital role in the progression and development of Atherosclerosis that alter the metabolism of Fibro-fatty. Receptors of micro RNA proliferate and regulate endothelial activation and smooth cell Macrophages, monocytes, t-cell and natural killer cells involved in the boosting of the immune system to prevent the atherosclerotic lesion formation. In this review, we can know how RNA’s involved in the pathophysiology side of atherosclerosis and explore the mechanism to regulate Atherosclerosis, and how macrophages evoke an immune response. Therefore, the use of synthetic and natural drugs and following the right diet timely prevent and reduce the risk of development of Atherosclerosis.

Evaluation of Plaque Characteristics and Inflammation Using Magnetic Resonance Imaging

Atherosclerosis is an inflammatory disease of large and medium-sized arteries, characterized by the growth of atherosclerotic lesions (plaques). These plaques often develop at inner curvatures of arteries, branchpoints, and bifurcations, where the endothelial wall shear stress is low and oscillatory. In conjunction with other processes such as lipid deposition, biomechanical factors lead to local vascular inflammation and plaque growth. There is also evidence that low and oscillatory shear stress contribute to arterial remodeling, entailing a loss in arterial elasticity and, therefore, an increased pulse-wave velocity. Although altered shear stress profiles, elasticity and inflammation are closely intertwined and critical for plaque growth, preclinical and clinical investigations for atherosclerosis mostly focus on the investigation of one of these parameters only due to the experimental limitations. However, cardiovascular magnetic resonance imaging (MRI) has been demonstrated to be a potent tool which can be used to provide insights into a large range of biological parameters in one experimental session. It enables the evaluation of the dynamic process of atherosclerotic lesion formation without the need for harmful radiation. Flow-sensitive MRI provides the assessment of hemodynamic parameters such as wall shear stress and pulse wave velocity which may replace invasive and radiation-based techniques for imaging of the vascular function and the characterization of early plaque development. In combination with inflammation imaging, the analyses and correlations of these parameters could not only significantly advance basic preclinical investigations of atherosclerotic lesion formation and progression, but also the diagnostic clinical evaluation for early identification of high-risk plaques, which are prone to rupture. In this review, we summarize the key applications of magnetic resonance imaging for the evaluation of plaque characteristics through flow sensitive and morphological measurements. The simultaneous measurements of functional and structural parameters will further preclinical research on atherosclerosis and has the potential to fundamentally improve the detection of inflammation and vulnerable plaques in patients.

Nilotinib activates endothelial TLR4 to exacerbate atherosclerosis

The use of nilotinib (Tasigna®), a second-generation tyrosine kinase inhibitor for treating chronic myeloid leukemia, increases risks for atherosclerosis. Here, we demonstrate that in endothelial cells, nilotinib activated TLR4, triggerd expression of inflammatory molecules, and increased monocyte attachment, which were all inhibited by knockdown of TLR4 or TLR4 inhibitor, CLI-095. Orally administered nilotinib profoundly accelerated atherosclerotic lesion formation in ApoE−/− mice, while co-administration of CLI-095 effectively reduced lesion areas. Our findings reveal TLR4 activation as an underlying mechanism of the pro-atherosclerotic effect of nilotinib and suggest TLR4 inhibition as an effective therapeutic approach to address vascular safety issue of nilotinib.

Hematopoietic Deficiency of the Long Noncoding RNA MALAT1 Promotes Atherosclerosis and Plaque Inflammation

Background:The majority of the human genome comprises noncoding sequences, which are in part transcribed as long noncoding RNAs (lncRNAs). lncRNAs exhibit multiple functions, including the epigenetic control of gene expression. In this study, the effect of the lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) on atherosclerosis was examined.Methods:The effect of MALAT1 on atherosclerosis was determined in apolipoprotein E–deficient (Apoe−/−) MALAT1-deficient (Malat1−/−) mice that were fed with a high-fat diet and by studying the regulation of MALAT1 in human plaques.Results:Apoe−/−Malat1−/−mice that were fed a high-fat diet showed increased plaque size and infiltration of inflammatory CD45+cells compared with Apoe−/−Malat1+/+control mice. Bone marrow transplantation of Apoe−/−Malat1−/−bone marrow cells in Apoe−/−Malat1+/+mice enhanced atherosclerotic lesion formation, which suggests that hematopoietic cells mediate the proatherosclerotic phenotype. Indeed, bone marrow cells isolated from Malat1−/−mice showed increased adhesion to endothelial cells and elevated levels of proinflammatory mediators. Moreover, myeloid cells of Malat1−/−mice displayed enhanced adhesion to atherosclerotic arteries in vivo. The anti-inflammatory effects of MALAT1 were attributed in part to reduction of the microRNA miR-503. MALAT1 expression was further significantly decreased in human plaques compared with normal arteries and was lower in symptomatic versus asymptomatic patients. Lower levels of MALAT1 in human plaques were associated with a worse prognosis.Conclusions:Reduced levels of MALAT1 augment atherosclerotic lesion formation in mice and are associated with human atherosclerotic disease. The proatherosclerotic effects observed in Malat1−/−mice were mainly caused by enhanced accumulation of hematopoietic cells.