Atheroprotective Effects of Tumor Necrosis Factor–Stimulated Gene-6

Watanabe, Ryoji; Watanabe, Hidenobu; Takahashi, Yasuhiro; Kojima, Miho; Konii, Hanae; Watanabe, K.; Shirai, Ryuichi; Sato, Kengo; Matsuyama, Takehisa; Ishibashi‐Ueda, Hatsue; Iso, Yoshitaka; Koba, Shinji; Kobayashi, Youichi; Hirano, Tsutomu; Watanabe, Takuya

doi:10.1016/j.jacbts.2016.07.008

Cited by 28 publications

(45 citation statements)

References 40 publications

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“…HUVECs (Lonza, Basel, Switzerland) were incubated at 37°C in 5% CO 2 for 4 hours with an indicated concentration of KP‐10 in EGM‐2 (Lonza) containing 5% FBS. The mRNAs for TNF‐α, IL‐6, MCP‐1, ICAM‐1, VCAM‐1, E‐selectin, and glyceraldehyde‐3‐dehydrogenase were detected as described previously …”

Section: Methodsmentioning

confidence: 99%

“…Ten microliters of WST‐8 solution (Cell Count Reagent SF; Nacalai Tesque, Inc, Kyoto, Japan) were then added to each well. After 1 hour of incubation, the quantity of formazan product was determined by reading absorbance at 450 nm using a Sunrise Remote R‐micro plate reader (Tecan, Männedorf, Switzerland) …”

Section: Methodsmentioning

confidence: 99%

“…Aliquots of protein extracts (20 μg) derived from HMDMs, HASMCs, HUVECs, and EA.hy926 cells were separated by 10% SDS‐PAGE and then immunoblotted with antibodies raised against the following proteins: KP‐10; GPR54 (LifeSpan BioSciences, Seattle, WA); phosphorylated protein kinase B (p‐Akt); phosphorylated extracellular signal‐regulated kinase 1 and 2 (ERK1/2); phosphorylated p38 (Cell Signaling Technology, Danvers, MA); cleaved caspase‐3 (R&D Systems, Inc, Minneapolis, MN); and Bcl‐2‐associated X protein (Bax; Abcam, Cambridge, MA). Other antibodies used were same as described previously …”

Section: Methodsmentioning

confidence: 99%

“…Endothelial inflammation stimulates the production of proatherogenic adhesion molecules, such as tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), monocyte chemotactic protein‐1 (MCP‐1), intercellular adhesion molecule‐1 (ICAM‐1), vascular adhesion molecule‐1 (VCAM‐1), and E‐selectin in endothelial cells (ECs). These effectors encourage monocyte adhesion and infiltration into the intimal layer, followed by fatty streak formation that is attributed to an accumulation of lipid‐laden macrophage foam cells . Foam cell formation is characterized by the intracytoplasmic accumulation of cholesterol ester (CE), which is dependent on the balance between uptake of oxidized low‐density lipoprotein (oxLDL) by CD36 and efflux of free cholesterol (FC) controlled by ATP‐binding cassette transporter A1 (ABCA1) .…”

Section: Introductionmentioning

confidence: 99%

“…To protect the cells against the toxicity of excessive FC accumulation, FC is esterified to CE by acyl‐CoA:cholesterol acyltransferase‐1 (ACAT‐1). Other than the accumulation of macrophage foam cells, migration and proliferation of vascular smooth muscle cells (VSMCs), EC proliferation, and production of extracellular matrix (ECM) components, such as the collagens, matrix metalloproteinases (MMPs), fibronectin, and elastin, all contribute to progression of atherosclerotic plaques …”

Section: Introductionmentioning

confidence: 99%

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Potent Vasoconstrictor Kisspeptin‐10 Induces Atherosclerotic Plaque Progression and Instability: Reversal by its Receptor GPR54 Antagonist

Sato

Shirai

Hontani

et al. 2017

JAHA

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BackgroundKisspeptin‐10 (KP‐10), a potent vasoconstrictor and inhibitor of angiogenesis, and its receptor, GPR54, have currently received much attention in relation to pre‐eclampsia. However, it still remains unknown whether KP‐10 could affect atherogenesis.Methods and ResultsWe evaluated the effects of KP‐10 on human umbilical vein endothelial cells, human monocyte‐derived macrophages, human aortic smooth muscle cells in vitro, and atherosclerotic lesions in apolipoprotein E–deficient (ApoE−/−) mice in vivo. KP‐10 significantly increased the adhesion of human monocytes to human umbilical vein endothelial cells, which was significantly inhibited by pretreatment with P234, a GPR54 antagonist. KP‐10 stimulated mRNA expression of tumor necrosis factor‐α, interleukin‐6, monocyte chemotactic protein‐1, intercellular adhesion molecule‐1, vascular adhesion molecule‐1, and E‐selectin in human umbilical vein endothelial cells. KP‐10 significantly enhanced oxidized low‐density lipoprotein–induced foam cell formation associated with upregulation of CD36 and acyl‐CoA:cholesterol acyltransferase‐1 in human monocyte‐derived macrophages. In human aortic smooth muscle cells, KP‐10 significantly suppressed angiotensin II–induced migration and proliferation, but enhanced apoptosis and activities of matrix metalloproteinase (MMP)‐2 and MMP‐9 by upregulation of extracellular signal‐regulated kinase 1 and 2, p38, Bcl‐2‐associated X protein, and caspase‐3. Four‐week‐infusion of KP‐10 into ApoE−/− mice significantly accelerated the development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration and vascular inflammation as well as decreased intraplaque vascular smooth muscle cells contents. Proatherosclerotic effects of endogenous and exogenous KP‐10 were completely canceled by P234 infusion in ApoE−/− mice.ConclusionsOur results suggest that KP‐10 may contribute to accelerate the progression and instability of atheromatous plaques, leading to plaque rupture. The GPR54 antagonist may be useful for prevention and treatment of atherosclerosis. Thus, the KP‐10/GPR54 system may serve as a novel therapeutic target for atherosclerotic diseases.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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