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er stress and atherogenesis

Alexandre Moura-Assis, Milessa Silva Afonso, Vanessa de Oliveira, Joseane Morari, Gustavo Aparecido Dos Santos, Marcia Koike, Ana Maria Lottenberg, Rodrigo Ramos Catharino, Licio Augusto Velloso, Adelino Sanchez Ramos da Silva, L P de Moura, Eduardo Rochete Ropelle, José Rodrigo Pauli, Dennys Esper Corrêa Cintra
The "first hit" to atherogenesis is driven by toll-like receptor 4, endoplasmic reticulum stress and ultimately metabolic dysfunction. In this study, we hypothesized that a flaxseed oil-enriched diet (FS) abolishes these inflammatory signaling pathway and restore metabolic homeostasis by activating the fatty acid receptor GPR120 in aorta of obese mice. Glucose homeostasis was assessed by GTT and ITT; lipidomics was performed using a Hybrid Ion Trap-Orbitrap Mass Spectrometer; serum lipids were measured using colorimetric assays; GPR120 and infiltrating macrophages were analyzed by immunofluorescence; protein immunoprecipitation and gene expression were evaluated by Western blot and RT-PCR, respectively...
March 2018: Journal of Nutritional Biochemistry
Mingxue Di, Lin Wang, Mengmeng Li, Yu Zhang, Xinxin Liu, Renya Zeng, Han Wang, Yifei Chen, Weijia Chen, Yun Zhang, Mei Zhang
Several clinical studies reported that Dickkopf1 (DKK1) plasma levels are correlated with atherosclerosis. However, the impact of DKK1 on the formation and vulnerability of atherosclerotic plaques remains elusive. This study investigated DKK1's effects on enlargement and destabilization of plaques by targeting endothelial cells and assessing the possible cellular mechanisms involved. The effects of DKK1 on atherogenesis and plaque stability were evaluated in ApoE-/- mice using lentivirus injections to knockdown and knock-in the DKK1 gene...
July 13, 2017: Cell Death & Disease
Alberto Canfrán-Duque, Noemi Rotllan, Xinbo Zhang, Marta Fernández-Fuertes, Cristina Ramírez-Hidalgo, Elisa Araldi, Lidia Daimiel, Rebeca Busto, Carlos Fernández-Hernando, Yajaira Suárez
Atherosclerosis, the major cause of cardiovascular disease, is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells in the artery wall. Aberrant expression of microRNAs has been implicated in the pathophysiological processes underlying the progression of atherosclerosis. Here, we define the contribution of miR-21 in hematopoietic cells during atherogenesis. Interestingly, we found that miR-21 is the most abundant miRNA in macrophages and its absence results in accelerated atherosclerosis, plaque necrosis, and vascular inflammation...
September 2017: EMBO Molecular Medicine
Zahra Hoseini, Fatemeh Sepahvand, Bahman Rashidi, Amirhossein Sahebkar, Aria Masoudifar, Hamed Mirzaei
Inflammasomes are intracellular complexes involved in the innate immunity that convert proIL-1β and proIL-18 to mature forms and initiate pyroptosis via cleaving procaspase-1. The most well-known inflammasome is NLRP3. Several studies have indicated a decisive and important role of NLRP3 inflammasome, IL-1β, IL-18, and pyroptosis in atherosclerosis. Modern hypotheses introduce atherosclerosis as an inflammatory/lipid-based disease and NLRP3 inflammasome has been considered as a link between lipid metabolism and inflammation because crystalline cholesterol and oxidized low-density lipoprotein (oxLDL) (two abundant components in atherosclerotic plaques) activate NLRP3 inflammasome...
March 2018: Journal of Cellular Physiology
Nhat-Tu Le, Uday G Sandhu, Raymundo A Quintana-Quezada, Nguyet Minh Hoang, Keigi Fujiwara, Jun-Ichi Abe
Atherosclerosis rarely develops in the region of arteries exposed to undisturbed flow (u-flow, unidirectional flow). Instead, atherogenesis occurs in the area exposed to disturbed flow (d-flow, multidirectional flow). Based on these general pathohistological observations, u-flow is considered to be athero-protective, while d-flow is atherogenic. The fact that u-flow and d-flow induce such clearly different biological responses in the wall of large arteries indicates that these two types of flow activate each distinct intracellular signaling cascade in vascular endothelial cells (ECs), which are directly exposed to blood flow...
May 2017: Cellular and Molecular Life Sciences: CMLS
MacRae F Linton, Vladimir R Babaev, Jiansheng Huang, Edward F Linton, Huan Tao, Patricia G Yancey
Macrophage apoptosis and the ability of macrophages to clean up dead cells, a process called efferocytosis, are crucial determinants of atherosclerosis lesion progression and plaque stability. Environmental stressors initiate endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR). Unresolved ER stress with activation of the UPR initiates apoptosis. Macrophages are resistant to apoptotic stimuli, because of activity of the PI3K/Akt pathway. Macrophages express 3 Akt isoforms, Akt1, Akt2 and Akt3, which are products of distinct but homologous genes...
October 25, 2016: Circulation Journal: Official Journal of the Japanese Circulation Society
Marc Clément, Gemma Basatemur, Leanne Masters, Lauren Baker, Patrick Bruneval, Takao Iwawaki, Manfred Kneilling, Sho Yamasaki, Jane Goodall, Ziad Mallat
BACKGROUND: Atherosclerotic lesion expansion is characterized by the development of a lipid-rich necrotic core known to be associated with the occurrence of complications. Abnormal lipid handling, inflammation, and alteration of cell survival or proliferation contribute to necrotic core formation, but the molecular mechanisms involved in this process are not properly understood. C-type lectin receptor 4e (Clec4e) recognizes the cord factor of Mycobacterium tuberculosis but also senses molecular patterns released by necrotic cells and drives inflammation...
October 4, 2016: Circulation
Manuel Vázquez-Carrera
Insulin resistance precedes dyslipidemia and type 2 diabetes mellitus (T2DM) development. Preclinical evidence suggests that peroxisome proliferator-activated receptor (PPAR) β/δ activators may prevent and treat obesity-induced insulin resistance and T2DM, while clinical trials highlight their potential utility in dyslipidemia. This review summarizes recent mechanistic insights into the antidiabetic effects of PPARβ/δ activators, including their anti-inflammatory actions, their ability to inhibit endoplasmic reticulum (ER) stress and hepatic lipogenesis, and to improve atherogenesis and insulin sensitivity, as well as their capacity to activate pathways that are also stimulated by exercise...
May 2016: Trends in Endocrinology and Metabolism: TEM
Fangfang Liu, Wen Cheng, Xiaolei Bi, Yun Zhang, Yuxia Zhao, Fan Jiang
Deletion of the gene of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in apolipoprotein E-deficient (ApoE-/-) mice increased atherosclerosis. However, the effect of TRAIL at a supra-physiological level on early atherogenesis is unknown. ApoE-/- mice were divided into Early (high-fat diet with concomitant TRAIL treatment for 4 weeks) and Late (high-fat diet for 16 weeks with TRAIL being given during the last 4 weeks) groups. It was found that TRAIL stimulated atherogenesis in the Early group but not in the Late group...
May 2016: Clinical and Experimental Pharmacology & Physiology
Sin-Hye Park, Min-Kyung Kang, Yean-Jung Choi, Yun-Ho Kim, Lucia Dwi Antika, Soon Sung Lim, Young-Hee Kang
SCOPE: Prolonged endoplasmic reticulum (ER) stress has lost the function of protein folding capacity and the ER accumulation of unfolded proteins that eventually triggers apoptosis. Oxysterols are emerging as contributing factors in atherogenesis known to involve macrophage apoptosis. This study determined the inhibitory effect of α-asarone present in purple perilla, on 7β-hydroxycholesterol-induced macrophage apoptosis, targeting against ER stress signaling pathway. METHODS AND RESULTS: J774A1 murine macrophages were exposed to 28 μM 7β-hydroxycholesterol and treated with 1-10 μM α-asarone...
May 2016: Molecular Nutrition & Food Research
Luciano Cominacini, Ulisse Garbin, Chiara Mozzini, Chiara Stranieri, Andrea Pasini, Erika Solani, Irene Alessandra Tinelli, Anna Fratta Pasini
Although the understanding the pathophysiology of atherogenesis and atherosclerosis progression has been one of the major goals of cardiovascular research during the last decades, the precise mechanisms underlying plaque destabilization are still unknown. The disruption of the plaque and the thrombosis in the lumen that are mostly determined by the expansion of the necrotic core (NC) are driven by various mechanisms, including accelerated macrophage apoptosis and defective phagocytic clearance (defective efferocytosis)...
2015: Current Medicinal Chemistry
Qiang Cao, Xianfeng Wang, Lin Jia, Ashis K Mondal, Abdoulaye Diallo, Gregory A Hawkins, Swapan K Das, John S Parks, Liqing Yu, Huidong Shi, Hang Shi, Bingzhong Xue
Inflammation marks all stages of atherogenesis. DNA hypermethylation in the whole genome or specific genes is associated with inflammation and cardiovascular diseases. Therefore, we aimed to study whether inhibiting DNA methylation by DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) ameliorates atherosclerosis in low-density lipoprotein receptor knockout (Ldlr(-/-)) mice. Ldlr(-/-) mice were fed an atherogenic diet and adminisered saline or 5-aza-dC (0.25 mg/kg) for up to 30 weeks. 5-aza-dC treatment markedly decreased atherosclerosis development in Ldlr(-/-) mice without changes in body weight, plasma lipid profile, macrophage cholesterol levels and plaque lipid content...
December 2014: Endocrinology
Dan Hong, Hai-Chao Gao, Xiang Wang, Ling-Fang Li, Chuan-Chang Li, Ying Luo, Kang-Kai Wang, Yong-Ping Bai, Guo-Gang Zhang
Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is emerging as a key contributing factor in atherogenesis, a process in turn known to involve macrophage apoptosis. The aim of this study was to determine the effect of ADMA on macrophage apoptosis, with specific reference to the endoplasmic reticulum (ER) stress pathway. Macrophage apoptosis was evaluated by Annexin V- Propidium iodide (PI) and Hoechst 33258 staining assays. Levels of the ER stress marker glucose regulated protein 78 (GRP78) were characterized by western blot...
January 2015: Molecular and Cellular Biochemistry
Robert H Lee, Guillermo Vazquez
Recent observations in endothelial cells and macrophages indicate that nicotinic acetylcholine receptors (nAChRs) are potential novel players in mechanisms linked to atherogenesis. In macrophages, α7nAChR mediates anti-inflammatory actions and contributes to regulation of cholesterol flux and phagocytosis. Considering that macrophage apoptosis is a key process throughout all stages of atherosclerotic lesion development, in the present study, we examined for the first time the impact of α7nAChR expression and function in macrophage survival and apoptosis using in vitro polarized (M1 and M2) bone marrow-derived macrophages (BMDMs) from wild-type and α7nAChR knockout mice...
December 1, 2013: Physiological Reports
Chaoyong He, Huaiping Zhu, Wencheng Zhang, Imoh Okon, Qilong Wang, Hongliang Li, Yun-Zheng Le, Zhonglin Xie
Oxidized lipoproteins stimulate autophagy in advanced atherosclerotic plaques. However, the mechanisms underlying autophagy induction and the role of autophagy in atherogenesis remain to be determined. This study was designed to investigate the mechanisms by which 7-ketocholesterol (7-KC), a major component of oxidized lipoproteins, induces autophagy. This study was also designed to determine the effect of autophagy induction on apoptosis, a central event in the development of atherosclerosis. Exposure of human aortic smooth muscle cells to 7-KC increased autophagic flux...
August 2013: American Journal of Pathology
Nilima Shukla, Song Wan, Gianni D Angelini, Jamie Y Jeremy
Thapsigargin (TG), an inhibitor of Ca(2+) ATPase pumps in the endoplasmic reticulum (ER), inhibits replication of human vascular smooth muscle cell (hVSMC) at low nM concentrations. TG blocks replication of other cell types through promotion of ER stress (ERS). In order to determine whether ERS may mediate the cytostatic effect of TG in hVSMCs, the effect of TG on ERS in hVSMCs was studied by assessing markers of ERS: Immunoglobulin Heavy Chain Binding Protein (BiP), growth inhibitory transcription factor, GADD153, phosphorlylated eukaryotic initiation factor 2α (p-eIF2α) and phosphorlylated protein kinase R (p-PKR)...
August 15, 2013: European Journal of Pharmacology
Gazi S Hossain, Edward G Lynn, Kenneth N Maclean, Ji Zhou, Jeffrey G Dickhout, Sárka Lhoták, Bernardo Trigatti, John Capone, Jaerang Rho, Damu Tang, Christopher A McCulloch, Imtisal Al-Bondokji, Mary J Malloy, Clive R Pullinger, John P Kane, Yonghong Li, Dov Shiffman, Richard C Austin
BACKGROUND: Apoptosis caused by endoplasmic reticulum (ER) stress contributes to atherothrombosis, the underlying cause of cardiovascular disease (CVD). T-cell death-associated gene 51 (TDAG51), a member of the pleckstrin homology-like domain gene family, is induced by ER stress, causes apoptosis when overexpressed, and is present in lesion-resident macrophages and endothelial cells. METHODS AND RESULTS: To study the role of TDAG51 in atherosclerosis, male mice deficient in TDAG51 and apolipoprotein E (TDAG51(-/-)/ApoE(-/-)) were generated and showed reduced atherosclerotic lesion growth (56 ± 5% reduction at 40 weeks, relative to ApoE(-/-) controls, P<0...
June 2013: Journal of the American Heart Association
Peter F Davies, Mete Civelek, Yun Fang, Ingrid Fleming
Atherosclerosis initiates at predictable focal sites and develops to a spatially regional disease with limited distribution. There is compelling evidence that links haemodynamics to the localized origin of atherosclerotic lesions. Arterial flow in vivo is unsteady, dynamically complex, and regionally variable. Sites susceptible to atherosclerosis near arterial branches and curves are associated with regions of disturbed blood flow that contain repetitive phases of flow reversal resulting in steep multidirectional temporal and spatial gradients of wall shear stresses...
July 15, 2013: Cardiovascular Research
P Larroque-Cardoso, A Swiader, C Ingueneau, A Nègre-Salvayre, M Elbaz, M E Reyland, R Salvayre, C Vindis
During atherogenesis, excess amounts of low-density lipoproteins (LDL) accumulate in the subendothelial space where they undergo oxidative modifications. Oxidized LDL (oxLDL) alter the fragile balance between survival and death of vascular smooth muscle cells (VSMC) thereby leading to plaque instability and finally to atherothrombotic events. As protein kinase C δ (PKCδ) is pro-apoptotic in many cell types, we investigated its potential role in the regulation of VSMC apoptosis induced by oxLDL. We found that human VSMC silenced for PKCδ exhibited a protection towards oxLDL-induced apoptosis...
February 28, 2013: Cell Death & Disease
Carole Muller, Jan Bandemer, Cecile Vindis, Caroline Camaré, Elodie Mucher, Françoise Guéraud, Pauline Larroque-Cardoso, Corinne Bernis, Nathalie Auge, Robert Salvayre, Anne Negre-Salvayre
AIMS: Protein disulfide isomerase (PDI) is an abundant endoplasmic reticulum (ER)-resident chaperone and oxidoreductase that catalyzes formation and rearrangement (isomerization) of disulfide bonds, thereby participating in protein folding. PDI modification by nitrosative stress is known to increase protein misfolding, ER stress, and neuronal apoptosis. As LDL oxidation and ER stress may play a role in atherogenesis, this work was designed to investigate whether PDI was inactivated by oxLDLs, thereby participating in oxLDL-induced ER stress and apoptosis...
March 1, 2013: Antioxidants & Redox Signaling
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