| 1. |
- Björkegren, Johan L M, et al.
(author)
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Plasma cholesterol-induced lesion networks activated before regression of early, mature, and advanced atherosclerosis.
- 2014
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 10:2
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Journal article (peer-reviewed)abstract
- Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (≥80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr(-/-)Apob (100/100) Mttp (flox/flox)Mx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with regression-resistant, relatively unstable plaque remnants. Atherosclerosis genes responding to PCL before regression, unlike those responding to the regression itself, were enriched in inherited risk for coronary artery disease and myocardial infarction, indicating causality. Inference of transcription factor (TF) regulatory networks of these PCL-responsive gene sets revealed largely different networks in early, mature, and advanced lesions. In early lesions, PPARG was identified as a specific master regulator of the PCL-responsive atherosclerosis TF-regulatory network, whereas in mature and advanced lesions, the specific master regulators were MLL5 and SRSF10/XRN2, respectively. In a THP-1 foam cell model of atherosclerosis regression, siRNA targeting of these master regulators activated the time-point-specific TF-regulatory networks and altered the accumulation of cholesterol esters. We conclude that PCL leads to complete atherosclerosis regression only in mice with early lesions. Identified master regulators and related PCL-responsive TF-regulatory networks will be interesting targets to enhance PCL-mediated regression of mature and advanced atherosclerotic lesions.
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| 2. |
- Rossignoli, Aranzazu, et al.
(author)
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Plasma cholesterol lowering in an AngII-infused atherosclerotic mouse model with moderate hypercholesterolemia
- 2018
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In: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 42:1, s. 471-478
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Journal article (peer-reviewed)abstract
- Atherosclerosis is the main underlying causes of cardiovascular disease. There is a well‑established association between high blood cholesterol levels and the extent of atherosclerosis. Furthermore, atherosclerosis has been proposed to augment abdominal aortic aneurysm (AAA) formation. As patients with AAA often have parallel atherosclerotic disease and are therefore often on cholesterol‑lowering therapy, it is not possible to fully address the independent effects of plasma cholesterol lowering (PCL) treatment on AAA. The present study investigated the effect of angiotensin II (AngII)‑infusion in modestly hypercholesterolemic Ldlr‑/‑Apob100/100Mttpflox/floxMx1‑Cre mice with or without PCL treatment on a morphological and molecular level, in terms of atherosclerosis and AAA development. AngII infusion in the study mice resulted in an increased atherosclerotic lesion area and increased infiltration of inflammatory leukocytes, which was not observed in mice with PCL induced prior to AngII infusion. This suggested that AngII infusion in this mouse model induced atherosclerosis development, and that plasma cholesterol levels represent a controlling factor. Furthermore, AngII infusion in Ldlr‑/‑Apob100/100Mttpflox/floxMx1‑Cre mice caused a modest aneurysmal phenotype, and no differences in AAA development were observed between the different study groups. However, the fact that modest hypercholesterolemic mice did not develop AAA in a classical aneurysmal model indicated that plasma cholesterol levels are important for disease development.
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| 3. |
- Rossignoli, M Aránzazu
(author)
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Novel aspects of atherosclerosis : focusing on new target genes and the effect of cholesterol-lowering
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Atherosclerosis is most often the main underlying cause of cardiovascular diseases (CVDs), accounting for more than 31% of all deaths worldwide. It is driven by the uptake of low-density lipoproteins (LDL) by a dysfunctional arterial endothelium. It involves a complex interplay of genetic and cellular factors that result in an uncontrolled inflammatory response which can potentially be fatal. The main treatment for atherosclerosis is cholesterol-lowering drugs, statins. Despite their use, clinical events still occur. In this thesis, three papers regarding CVDs and some of the key events happening during atherosclerosis are discussed. In paper I the role of Lim domain-binding 2 (Ldb2) as a master regulator of transendothelial migration of leukocytes (TEML) during atherosclerosis was investigated. We described its function as a modulator of the leukocyte extravasation process using in vivo mouse models and in vitro systems. By examining Ldb2-deficient mice we found increased atherosclerotic lesions and decreased plaque stability. Their TEML activity was increased, especially regarding monocytes and macrophages, the principal initiators of the atherosclerotic process. Additionally, the role of this gene was reinforced by a functional SNP found in coronary artery disease (CAD) cohorts associated with increased risk of myocardial infarction (MI). In the following publication, paper II, we describe the function of the newly identified cholesterol-responsive gene Poliovirus receptor-related 2 (PVRL2) in atherosclerosis. This gene, as a member of the nectin family, plays a major role during TEML in the extravasation step. Regarding atherosclerosis development, Pvrl2-deficient mice showed fewer lesions and more stable plaques. An increased endothelial expression of Pvrl2 coincided with an increase in leukocyte gene expression, strengthening its potential role during TEML. In fact, we found a significant decrease in leukocyte migration in the Pvrl2-deficient mice using in vivo assays. Moreover, we observed its endothelial expression and cholesterol-responsiveness in humans. The effect of cholesterol-lowering on atherosclerosis is well established, and statins remain the main treatment. Since statins are prescribed to most CVD patients due to the underlying atherosclerosis, their specific effect on single diseases are not well studied. In paper III we aimed to identify the effect of angiotensin II (AngII)-induced AAA on atherosclerosis and the influence of cholesterol-lowering on abdominal aortic aneurysm (AAA) in an atherosclerotic mouse model. We found a low incidence of AAA formation after AngII infusion, possibly because the levels of cholesterol in our mice were not high enough. Nevertheless, AngII was found to enhance atherosclerosis and leukocyte infiltration, stressing the importance of the renin-angiotensin system on atherosclerosis and suggesting a controlling effect of cholesterol in the model. All three papers emphasize the importance of cholesterol during CVDs. Further research in order to elucidate the underlying mechanisms and detailed role of the identified gene targets could have a major impact on the development of new drugs. These could act directly on the TEML process, thus modulating the inflammatory response and attenuating disease complications.
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| 4. |
- Shang, Ming-Mei, et al.
(author)
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Lim domain binding 2 : a key driver of transendothelial migration of leukocytes and atherosclerosis
- 2014
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In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 34:9, s. 2068-2077
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Using a multi-tissue, genome-wide gene expression approach, we recently identified a gene module linked to the extent of human atherosclerosis. This atherosclerosis module was enriched with inherited risk for coronary and carotid artery disease (CAD) and overlapped with genes in the transendothelial migration of leukocyte (TEML) pathway. Among the atherosclerosis module genes, the transcription cofactor Lim domain binding 2 (LDB2) was the most connected in a CAD vascular wall regulatory gene network. Here, we used human genomics and atherosclerosis-prone mice to evaluate the possible role of LDB2 in TEML and atherosclerosis.APPROACH AND RESULTS: mRNA profiles generated from blood macrophages in patients with CAD were used to infer transcription factor regulatory gene networks; Ldlr(-/-)Apob(100/100) mice were used to study the effects of Ldb2 deficiency on TEML activity and atherogenesis. LDB2 was the most connected gene in a transcription factor regulatory network inferred from TEML and atherosclerosis module genes in CAD macrophages. In Ldlr(-/-)Apob(100/100) mice, loss of Ldb2 increased atherosclerotic lesion size ≈2-fold and decreased plaque stability. The exacerbated atherosclerosis was caused by increased TEML activity, as demonstrated in air-pouch and retinal vasculature models in vivo, by ex vivo perfusion of primary leukocytes, and by leukocyte migration in vitro. In THP1 cells, migration was increased by overexpression and decreased by small interfering RNA inhibition of LDB2. A functional LDB2 variant (rs10939673) was associated with the risk and extent of CAD across several cohorts.CONCLUSIONS: As a key driver of the TEML pathway in CAD macrophages, LDB2 is a novel candidate to target CAD by inhibiting the overall activity of TEML.
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