Toll-like receptor 2 plays a critical role in the progression of atherosclerosis that is independent of dietary lipids

Li, Xinyan; Ukai, Takashi; Yumoto, Hiromichi; Davey, Michael P.; Goswami, Sulip; Gibson, Frank C.; Genco, Caroline Attardo

doi:10.1016/j.atherosclerosis.2007.03.025

Cited by 140 publications

(109 citation statements)

References 37 publications

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“…TLR2 and TLR4 have been implicated in the signaling mechanisms that contribute to chronic inflammatory diseases, including atherosclerosis (7)(8)(9). A number of studies found that TLRs, particularly TLR2 and TLR4, also respond to endogenous agents, such as heat shock proteins (29 -32).…”

Section: Discussionmentioning

confidence: 99%

“…Yellow fluorescent protein (YFP)-TLR fusion protein expression constructs in pcDNA3 were obtained from Addgene (Cambridge, MA; plasmids 13018 (YFP-TLR4) and 13016 (YFP-TLR2)). The functionality of these receptor constructs has been demonstrated (9). All plasmids were isolated with EndoFree Maxi kits (Qiagen).…”

Section: Methodsmentioning

confidence: 99%

“…Neutralization of TLR2 or TLR4 Reduces OxLDL-induced BMP-2 Expression in Human CAECs-Several studies have linked TLR2 and TLR4 to atherosclerosis (7)(8)(9). Interestingly, minimally modified LDL induces macrophage actin polymerization and cell spreading via a TLR4-dependent mechanism (14).…”

Section: Oxldl Induces a Pro-osteogenic Response In Human Caecs-mentioning

confidence: 99%

“…Native LDL and electronegative LDL increase the expression and release of interleukin (IL)-8, monocyte chemoattractant protein-1, and IL-6 in human umbilical artery endothelial cells (6). TLR2 and TLR4 play important roles in the vascular inflammatory response and are involved in the initiation and progression of atherosclerosis (7)(8)(9)(10). Increased endothelial expression of TLR2 at sites of disturbed blood flow exacerbates early atherogenic events (11).…”

mentioning

confidence: 99%

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Oxidized Low Density Lipoprotein Induces Bone Morphogenetic Protein-2 in Coronary Artery Endothelial Cells via Toll-like Receptors 2 and 4

Shi

et al. 2011

Journal of Biological Chemistry

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Vascular calcification is a common complication in atherosclerosis. Bone morphogenetic protein-2 (BMP-2) plays an important role in atherosclerotic vascular calcification. The aim of this study was to determine the effect of oxidized low density lipoprotein (oxLDL) on BMP-2 protein expression in human coronary artery endothelial cells (CAECs), the roles of Toll-like receptor (TLR) 2 and TLR4 in oxLDL-induced BMP-2 expression, and the signaling pathways involved. Human CAECs were stimulated with oxLDL. The roles of TLR2 and TLR4 in oxLDLinduced BMP-2 expression were determined by pretreatment with neutralizing antibody, siRNA, and overexpression. Stimulation with oxLDL increased cellular BMP-2 protein levels in a dose-dependent manner (40 -160 g/ml). Pretreatment with neutralizing antibodies against TLR2 and TLR4 or silencing of these two receptors reduced oxLDL-induced BMP-2 expression. Overexpression of TLR2 and TLR4 enhanced the cellular BMP-2 response to oxLDL. Furthermore, oxLDL was co-localized with TLR2 and TLR4. BMP-2 expression was associated with activation of nuclear factor-B (NF-B), p38 mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase (ERK)1/2. Inhibition of NF-B and ERK1/2 reduced BMP-2 expression whereas inhibition of p38 MAPK had no effect. In conclusion, oxLDL induces BMP-2 expression through TLR2 and TLR4 in human CAECs. The NF-B and ERK1/2 pathways are involved in the signaling mechanism. These findings underscore an important role for TLR2 and TLR4 in mediating the BMP-2 response to oxLDL in human CAECs and indicate that these two immunoreceptors contribute to the mechanisms underlying atherosclerotic vascular calcification.Calcification in intima is often associated with atherosclerosis. Atherosclerotic calcification of coronary artery is a significant risk for the unsuccessful coronary intervention and balloon-induced coronary artery dissection (1), and calcification is found to be an indicator of plaque instability (2). Although inhibition of atherosclerotic calcification might be a promising approach to stabilize atherosclerotic plaques, the molecular mechanism(s) underlying atherosclerotic vascular calcification remains incompletely understood.It is known that oxLDL 2 accumulation in the vascular wall provokes the development of atherosclerosis and vascular calcification (3). BMP-2 is an osteogenic factor. It is expressed in calcified human atherosclerotic plaque. Cells from the atherogenic aortic wall express BMP-2 in vitro and formed calcified nodules with prolonged culture (4). The BMP-2 mRNA level increased after oxLDL stimulation in human CAECs (5). However, it remains unclear whether oxLDL up-regulates BMP-2 protein levels in CAECs. Further, the signaling mechanism that regulates the cellular BMP-2 response to oxLDL is unknown.Accumulating evidence indicates that atherosclerosis is an inflammatory process involving a network of vascular cells, monocytes, and T lymphocytes. Proinflammatory mediators, including cytokines, chemokines, and growth factors...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Oxldl Induces a Pro-osteogenic Response In Human Caecs-mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Oxidized Low Density Lipoprotein Induces Bone Morphogenetic Protein-2 in Coronary Artery Endothelial Cells via Toll-like Receptors 2 and 4

Shi

et al. 2011

Journal of Biological Chemistry

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“…36 Using the ApoE À/À mouse model, it has been shown that triggering TLR2 activation dramatically increases atherosclerotic plaque formation. 37 Furthermore, atherosclerotic plaque formation is significantly reduced in TLR4 À/À /ApoE À/À mice. 38 TLR2 and TLR4 signaling is involved not only in the development of Figure 4 Neointimal formation, Ang-2 and p47 phox expression in high fat-diet fed ApoE KO mice.…”

Section: Disscussionmentioning

confidence: 99%

Critical role of the NADPH oxidase subunit p47phox on vascular TLR expression and neointimal lesion formation in high-fat diet-induced obesity

Chen

Stinnett

2008

Laboratory Investigation

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Reactive oxygen species (ROS) formation is associated with inflammation and vasculature dysfunction. We investigated the potential role of the NADPH oxidase on vascular Toll-like receptor (TLR) expression and carotid neointimal formation in high-fat (HF) diet-induced obesity (DIO) model. Using mice DIO and common carotid artery flow cessation-induced lesion formation models, we examined vascular TLR2 and TLR4 expression and neointimal formation in NADPH oxidase subunit p47 phox -deficient (p47 phox-/-) mice. Feeding C57BL/6J mice an HF diet for 22 weeks resulted in significant increases in p47 phox , TLR2 and TLR4 expression in vascular tissues compared with mice fed a low-fat (LF) diet. Minimal changes in TLR2 and TLR4 expression was detected in p47 phox-/-DIO mice. Furthermore, flow cessation-induced angiogenic and inflammatory response and neointimal formation were significantly attenuated in p47 phoxÀ/À DIO mice compared with wild-type DIO mice. In addition, exposure of endothelial cells to leptin led to ROS formation; this was accompanied by upregulation of TLR2, TLR4 expression and its downstream signaling. Leptin also increased endothelial cell migration and proliferation. Pharmacological inhibition of NADPH oxidase or genetic deletion of p47 phox significantly diminished these alterations. Obesity increases neointimal formation via a mechanism involving p47 phox -TLRs signaling, suggesting that the NADPH oxidase may represent a potential novel therapeutic target for the treatment of obesity-associated vascular inflammation and dysfunction.

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Innate Immunity in Atherosclerosis

Chen

Shah

Arditi

2012

Inflammatory Diseases of Blood Vessels

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Toll-like receptor 2 plays a critical role in the progression of atherosclerosis that is independent of dietary lipids

Abstract: TLR2 plays a critical role in the progression of atherosclerosis in Apoe(-/-) mice, which is independent of dietary lipids and macrophage lipid uptake.

Cited by 140 publications

References 37 publications

Oxidized Low Density Lipoprotein Induces Bone Morphogenetic Protein-2 in Coronary Artery Endothelial Cells via Toll-like Receptors 2 and 4

Oxidized Low Density Lipoprotein Induces Bone Morphogenetic Protein-2 in Coronary Artery Endothelial Cells via Toll-like Receptors 2 and 4

Critical role of the NADPH oxidase subunit p47phox on vascular TLR expression and neointimal lesion formation in high-fat diet-induced obesity

Innate Immunity in Atherosclerosis

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