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Gene expression in atherosclerotic plaque culture

Kristiina Rajamäki, Mikko I Mäyränpää, Ana Risco, Jarno Tuimala, Katariina Nurmi, Ana Cuenda, Kari K Eklund, Katariina Öörni, Petri T Kovanen
OBJECTIVE: Activation of the inflammasome pathway in macrophages results in the secretion of 2 potent proinflammatory and proatherogenic cytokines, interleukin (IL)-1β, and IL-18. Atherosclerotic lesions are characterized by the presence of various endogenous activators of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, including cholesterol crystals and extracellular ATP. The aim of this study was to comprehensively characterize the expression of inflammasome pathway components and regulators in human atherosclerotic lesions...
September 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Jing-Jing Yang, Peng Li, Fu Wang, Wen-Jing Liang, Hui Ma, Yuan Chen, Zhi-Min Ma, Quan-Zhong Li, Qi-Sheng Peng, Yun Zhang, Shuang-Xi Wang
AIMS: Aspirin has been used for the secondary prevention and treatment of cardiovascular disease for several decades. We investigated the roles of transcriptional factor activator protein 2α (AP-2α) in the beneficial effects of aspirin in the growth and vulnerability of atherosclerotic plaque. METHODS AND RESULTS: In mice deficient of apolipoprotein E (Apoe-/-), aspirin (20, 50 mg/kg/day) suppressed the progression of atherosclerosis in aortic roots and increased the plaque stability in carotid atherosclerotic plaques induced by collar-placement...
July 4, 2016: Oncotarget
Wei Yang, Fu Liang Ng, Kenneth Chan, Xiangyuan Pu, Robin N Poston, Meixia Ren, Weiwei An, Ruoxin Zhang, Jingchun Wu, Shunying Yan, Haiteng Situ, Xinjie He, Yequn Chen, Xuerui Tan, Qingzhong Xiao, Arthur T Tucker, Mark J Caulfield, Shu Ye
Genome-wide association studies have revealed an association between coronary heart disease (CHD) and genetic variation on chromosome 13q34, with the lead single nucleotide polymorphism rs4773144 residing in the COL4A2 gene in this genomic region. We investigated the functional effects of this genetic variant. Analyses of primary cultures of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) from different individuals showed a difference between rs4773144 genotypes in COL4A2 and COL4A1 expression levels, being lowest in the G/G genotype, intermediate in A/G and highest in A/A...
July 2016: PLoS Genetics
Wei Xie, Liang Li, Min Zhang, Hai-Peng Cheng, Duo Gong, Yun-Cheng Lv, Feng Yao, Ping-Ping He, Xin-Ping Ouyang, Gang Lan, Dan Liu, Zhen-Wang Zhao, Yu-Lin Tan, Xi-Long Zheng, Wei-Dong Yin, Chao-Ke Tang
Atherosclerotic lesions are lipometabolic disorder characterized by chronic progressive inflammation in arterial walls. Previous studies have shown that macrophage-derived lipoprotein lipase (LPL) might be a key factor that promotes atherosclerosis by accelerating lipid accumulation and proinflammatory cytokine secretion. Increasing evidence indicates that microRNA-27 (miR-27) has beneficial effects on lipid metabolism and inflammatory response. However, it has not been fully understood whether miR-27 affects the expression of LPL and subsequent development of atherosclerosis in apolipoprotein E knockout (apoE KO) mice...
2016: PloS One
Monica Madalina Tucureanu, Elena Butoi, Ana-Maria Gan, Daniela Stan, Cristina Ana Constantinescu, Manuela Calin, Maya Simionescu, Ileana Manduteanu
In atherosclerotic plaques, macrophages (MAC) and smooth muscle cells (SMC) frequently reside in close proximity and resistin (Rs) and fractalkine (Fk) are present at increased levels, resistin being associated with CD68 macrophages and fractalkine predominantly associated with intimal SMC; however, their role in this location is not clear, yet. The objective of this study was to determine whether the cross-talk between MAC-SMC induces changes in MAC cytokine phenotype and if Fk and Rs have a role in the process...
July 2016: Cytokine
Yusuke Higashi, Sergiy Sukhanov, Shaw-Yung Shai, Svitlana Danchuk, Richard Tang, Patricia Snarski, Zhaohui Li, Patricia Lobelle-Rich, Meifang Wang, Derek Wang, Hong Yu, Ronald Korthuis, Patrice Delafontaine
BACKGROUND: We have previously shown that systemic infusion of insulin-like growth factor-1 (IGF-1) exerts anti-inflammatory and antioxidant effects and reduces atherosclerotic burden in apolipoprotein E (Apoe)-deficient mice. Monocytes/macrophages express high levels of IGF-1 receptor (IGF1R) and play a pivotal role in atherogenesis, but the potential effects of IGF-1 on their function are unknown. METHODS AND RESULTS: To determine mechanisms whereby IGF-1 reduces atherosclerosis and to explore the potential involvement of monocytes/macrophages, we created monocyte/macrophage-specific IGF1R knockout (MΦ-IGF1R-KO) mice on an Apoe(-/-) background...
June 7, 2016: Circulation
Tobias Asdonk, Martin Steinmetz, Alexander Krogmann, Christine Ströcker, Catharina Lahrmann, Inga Motz, Kathrin Paul-Krahe, Anna Flender, Theresa Schmitz, Winfried Barchet, Gunther Hartmann, Georg Nickenig, Sebastian Zimmer
Recent studies have highlighted the relevance of viral nucleic acid immunorecognition by pattern recognition receptors in atherogenesis. Melanoma differentiation associated gene 5 (MDA-5) belongs to the intracellular retinoic acid inducible gene-I like receptors and its activation promotes pro-inflammatory mechanisms. Here, we studied the effect of MDA-5 stimulation in vascular biology. To gain insights into MDA-5 dependent effects on endothelial function, cultured human coronary artery endothelial cells (HCAEC) were transfected with the synthetic MDA-5 agonist polyIC (long double-stranded RNA)...
September 2016: Journal of Cellular and Molecular Medicine
Masato Furuhashi, Takahiro Fuseya, Masaki Murata, Kyoko Hoshina, Shutaro Ishimura, Tomohiro Mita, Yuki Watanabe, Akina Omori, Megumi Matsumoto, Takeshi Sugaya, Tsuyoshi Oikawa, Junichi Nishida, Nobuaki Kokubu, Marenao Tanaka, Norihito Moniwa, Hideaki Yoshida, Norimasa Sawada, Kazuaki Shimamoto, Tetsuji Miura
OBJECTIVE: Fatty acid-binding protein 4 (FABP4) is expressed in adipocytes and macrophages, and elevated circulating FABP4 level is associated with obesity-mediated metabolic phenotype. We systematically investigated roles of FABP4 in the development of coronary artery atherosclerosis. APPROACH AND RESULTS: First, by immunohistochemical analyses, we found that FABP4 was expressed in macrophages within coronary atherosclerotic plaques and epicardial/perivascular fat in autopsy cases and macrophages within thrombi covering ruptured coronary plaques in thrombectomy samples from patients with acute myocardial infarction...
May 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
N G Nikiforov, V J Makeev, N V Elizova, A N Orekhov
Monocytes were isolated from blood of patients belonging to three groups: those with normal intima-media thickness (IMT) of carotid arteries, patients with increased IMT and patients with atherosclerotic plaques. The degree of activation of the macrophages was determined by the concentration of the cytokine TNF-α and chemokine CCL18 in the culture medium. When comparing the average values of the concentrations of TNF-α and CCL18 for patients in all groups dramatic individual differences were revealed. These individual differences were found within each group and in the pool...
July 2015: Patologicheskaia Fiziologiia i èksperimental'naia Terapiia
Aleksandra Leszczynska, Aideen O'Doherty, Eric Farrell, Jana Pindjakova, Fergal J O'Brien, Timothy O'Brien, Frank Barry, Mary Murphy
The cellular and molecular basis of vascular calcification (VC) in atherosclerosis is not fully understood. Here, we investigate role of resident/circulating progenitor cells in VC and contribution of inflammatory plaque environment to this process. Vessel-derived stem/progenitor cells (VSCs) and mesenchymal stem cells (MSCs) isolated from atherosclerotic ApoE(-/-) mice showed significantly more in vitro osteogenesis and chondrogenesis than cells generated from control C57BL/6 mice. To assess their ability to form bone in vivo, cells were primed chondrogenically or cultured in control medium on collagen glycosaminoglycan scaffolds in vitro prior to subcutaneous implantation in ApoE(-/-) and C57BL/6 mice using a crossover study design...
April 2016: Stem Cells
Joshua A Dubland, Gordon A Francis
PURPOSE OF REVIEW: Smooth muscle cells (SMCs) form the thickened intimal layer in atherosclerosis-prone arteries in early life, and provide the initial site for retention and uptake of atherogenic lipoproteins. Here we review current knowledge regarding the importance of SMCs in the deposition of cholesterol in atherosclerotic plaque. RECENT FINDINGS: SMCs were found to comprise at least 50% of total foam cells in human coronary artery atherosclerosis, and exhibit a selective loss of expression of the cholesterol efflux promoter ATP-binding cassette transporter A1...
April 2016: Current Opinion in Lipidology
Li-Hao Huang, Elaina M Melton, Haibo Li, Paul Sohn, Maximillian A Rogers, Mary Jo Mulligan-Kehoe, Steven N Fiering, William F Hickey, Catherine C Y Chang, Ta-Yuan Chang
Acyl-CoA:cholesterol acyltransferase 1 (Acat1) converts cellular cholesterol to cholesteryl esters and is considered a drug target for treating atherosclerosis. However, in mouse models for atherosclerosis, global Acat1 knockout (Acat1(-/-)) did not prevent lesion development. Acat1(-/-) increased apoptosis within lesions and led to several additional undesirable phenotypes, including hair loss, dry eye, leukocytosis, xanthomatosis, and a reduced life span. To determine the roles of Acat1 in monocytes/macrophages in atherosclerosis, we produced a myeloid-specific Acat1 knockout (Acat1(-M/-M)) mouse and showed that, in the Apoe knockout (Apoe(-/-)) mouse model for atherosclerosis, Acat1(-M/-M) decreased the plaque area and reduced lesion size without causing leukocytosis, dry eye, hair loss, or a reduced life span...
March 18, 2016: Journal of Biological Chemistry
Rachel J Roth Flach, Athanasia Skoura, Anouch Matevossian, Laura V Danai, Wei Zheng, Christian Cortes, Samit K Bhattacharya, Myriam Aouadi, Nana Hagan, Joseph C Yawe, Pranitha Vangala, Lorena Garcia Menendez, Marcus P Cooper, Timothy P Fitzgibbons, Leonard Buckbinder, Michael P Czech
Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe(-/-) mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development...
2015: Nature Communications
Hao Yan, Ying Ma, Yan Li, Xiaohui Zheng, Ping Lv, Yuan Zhang, Jia Li, Meijuan Ma, Le Zhang, Congye Li, Rongqing Zhang, Feng Gao, Haichang Wang, Ling Tao
Toll-like receptor (TLR) 4 induced inflammation was reported to play an important role in atherosclerotic plaque stability. Recent studies indicated that insulin could inhibit inflammation by activating phosphatidylinositol 3-kinase-Akt-dependent (PI3K-Akt) signaling pathway. In the current study, we hypothesized that insulin would inhibit TLR4 induced inflammation via promoting PI3K-Akt activation, thus enhancing the stabilization of atherosclerotic plaques. In order to mimic the process of plaque formation, monocyte-macrophage lineage RAW264...
February 2016: Immunology Letters
Iolanda Lazaro, Ainhoa Oguiza, Carlota Recio, Beñat Mallavia, Julio Madrigal-Matute, Julia Blanco, Jesus Egido, Jose-Luis Martin-Ventura, Carmen Gomez-Guerrero
Heat shock proteins (HSPs) are induced by cellular stress and function as molecular chaperones that regulate protein folding. Diabetes impairs the function/expression of many HSPs, including HSP70 and HSP90, key regulators of pathological mechanisms involved in diabetes complications. Therefore, we investigated whether pharmacological HSP90 inhibition ameliorates diabetes-associated renal damage and atheroprogression in a mouse model of combined hyperglycemia and hyperlipidemia (streptozotocin-induced diabetic apolipoprotein E-deficient mouse)...
October 2015: Diabetes
Jing-Hong Zhou, Zhi-Yuan Pan, Yan-Fang Zhang, Wen-Yu Cui, Chao-Liang Long, Hai Wang
OBJECTIVE: To investigate the effects of non-neuronal muscarinic receptors (NNMR) stimulation on atherosclerosis and endothelial cells activation. METHODS: Atherosclerosis model was established in ApoE-/- mice by a high fat diet for 7 weeks. During the experimental periods, animals were received a low (7 mg/kg/d) or a high (21 mg/kg/d) dose of arecoline by gavage. At the termination of the treatments, serum total cholesterol and NO levels were measured, and the aorta morphology was analyzed by hematoxylin and eosin staining...
November 2014: Chinese Journal of Applied Physiology
Maria Cristina Vinci, Luca Piacentini, Mattia Chiesa, Federica Saporiti, Gualtiero I Colombo, Maurizio Pesce
The function of human circulating PACs has been described extensively. However, little focus has been placed on understanding how these cells differ in their functions in the presence of microenvironments mimicking vascular inflammation. We hypothesized that exposure to proinflammatory cytokines or the oxLDL, an autoantigen abundant in advanced atherosclerotic plaques, converts PACs into immune-modulating/proinflammatory cells. Hence, we examined the effect of oxLDL and inflammatory stimuli on their phenotype by use of a functional genomics model based on secretome and whole genome transcriptome profiling...
September 2015: Journal of Leukocyte Biology
Vanessa Frodermann, Gijs H M van Puijvelde, Laura Wierts, H Maxime Lagraauw, Amanda C Foks, Peter J van Santbrink, Ilze Bot, Johan Kuiper, Saskia C A de Jager
Modulation of immune responses may form a powerful approach to treat atherosclerosis. It was shown that clearance of apoptotic cells results in tolerance induction to cleared Ags by dendritic cells (DCs); however, this seems impaired in atherosclerosis because Ag-specific tolerance is lacking. This could result, in part, from decreased emigration of DCs from atherosclerotic lesions because of the high-cholesterol environment. Nonetheless, local induction of anti-inflammatory responses by apoptotic cell clearance seems to dampen atherosclerosis, because inhibition of apoptotic cell clearance worsens atherosclerosis...
March 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Ruijin Xu, Chenglong Bi, Jiantao Song, Lin Wang, Cheng Ge, Xinxin Liu, Mei Zhang
MicroRNA (miR)‑142‑5p is a member of the miR‑142 family, which have been shown to be associated with tumors, stem cells and disorders of the immune system. However, the role of miR‑142‑5p in atherosclerosis has yet to be investigated. In the present study, an atherosclerotic apolipoprotein E‑deficient (apoE‑/‑) mouse model was constructed and fed a high‑fat diet. The expression levels of miR‑142‑5p in the murine atherosclerotic plaques were detected by gene microarray analysis. In addition, an in vitro assay was used to determine the expression levels of miR‑142‑5p in human endothelial cells, smooth muscle cells and macrophages, which were treated with oxidized low‑density lipoprotein (ox‑LDL)...
May 2015: Molecular Medicine Reports
Amanda K Sampson, Jennifer C Irvine, Waled A Shihata, Dragana Dragoljevic, Natalie Lumsden, Olivier Huet, Tyrone Barnes, Thomas Unger, Ulrike M Steckelings, Garry L Jennings, Robert E Widdop, Jaye P F Chin-Dusting
BACKGROUND AND PURPOSE: Angiotensin AT2 receptors are upregulated in disease states such as atherosclerosis and blockade of the AT2 receptors exacerbates plaque formation. Direct stimulation of these receptors is anti-atherogenic but the mechanisms and pathways involved remain unknown. We examined the effect of direct AT2 receptor stimulation with Compound 21 (C21) on the leukocyte adhesion cascade in vitro, right through to plaque formation in vivo. EXPERIMENTAL APPROACH: Effects of C21 on TNFα-induced inflammation were assessed in human umbilical vein endothelial cells (HUVECs), activation of monocytes, polarisation of monocyte-derived macrophages and in intact mouse aortae...
February 2016: British Journal of Pharmacology
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