High glucose promotes intracellular lipid accumulation in vascular smooth muscle cells by impairing cholesterol influx and efflux balance

Xue, Jiangyu; Yuan, Zuyi; Wu, Yue; Liu, Yan; Zhao, Yan; Zhang, Weiping; Tian, Yuling; Liu, Weimin; Liu, Yu; Kishimoto, Chiharu

doi:10.1093/cvr/cvp388

Cited by 66 publications

(42 citation statements)

References 37 publications

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“…In the last decade, several studies have shown that in addition to macrophages, VSMCs accumulate excess intracellular cholesteryl (25,26) and give rise to a significant number of foam cells in atherosclerotic lesions (14,27). Moreover, VSMC-derived foam cells in vitro lose the expression of VSMC contractile markers, transform into macrophage-like cells (15) and express monocyte chemoattractant protein-1 (MCP-1) (16,28).…”

Section: Discussionmentioning

confidence: 99%

17β-estradiol promotes cholesterol efflux from vascular smooth muscle cells through a liver X receptor α-dependent pathway

Wang

Liu

Zhu

et al. 2014

International Journal of Molecular Medicine

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Abstract. Estrogen has pleiotropic effects on the cardiovascular diseases, yet the underlying mechanisms remain incompletely understood. Cholesterol efflux is a key mechanism through which to prevent foam cell formation and the development of atherosclerosis. Recent studies highlight the role of vascular smooth muscle cell (VSMC)-derived foam cells in atherogenesis. However, it remains unclear whether estrogen promotes cholesterol efflux from VSMCs and inhibits VSMC-derived foam cell formation. In the present study, we demonstrated that 17β-estradiol (E2) markedly enhanced cholesterol efflux to apolipoprotein (apo)A-1 and high-density lipoprotein (HDL) and attenuated oxidized low-density lipoprotein (ox-LDL) induced cholesteryl ester accumulation in VSMCs, which was associated with an increase in the expression of ATP-binding cassette transporters ABCA1 and ABCG1. The upregulation of ABCA1 and ABCG1 expression by E2 resulted from liver X receptor (LXR)α activation, which was confirmed by the prevention of the expression of ABCA1 and ABCG1 after inhibition of LXRα with a pharmacological inhibitor or small interfering RNA (siRNA). Furthermore, E2 increased LXRα, ABCA1 and ABCG1 expression in VSMCs via the estrogen receptor (ER), and the involvement of ERβ was confirmed by the use of selective ERα or ERβ antagonists (MPP and PHTPP) and agonists (PPT and DPN). These findings suggest that E2 promotes cholesterol efflux from VSMCs and reduces VSMCderived foam cell formation via ERβ-and LXRα-dependent upregulation of ABCA1 and ABCG1 and provide novel insights into the anti-atherogenic properties of estrogen.

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Section: Discussionmentioning

confidence: 99%

17β-estradiol promotes cholesterol efflux from vascular smooth muscle cells through a liver X receptor α-dependent pathway

Wang

Liu

Zhu

et al. 2014

International Journal of Molecular Medicine

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“…These studies, while showing a critical role for platelet CD36 in thrombosis, do not rule out a role for CD36-mediated signaling in other vascular cells in promoting thrombosis. Although CD36 is not expressed on large-vessel endothelial cells (5,6), several groups have reported that VSMCs in culture express low levels of CD36 (7)(8)(9)(10)(11)(12) and that expression can be upregulated by PPARγ (9). No function for CD36 has been identified, however, on VSMCs.…”

Section: Introductionmentioning

confidence: 99%

CD36 participates in a signaling pathway that regulates ROS formation in murine VSMCs

et al. 2010

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CD36 is a membrane glycoprotein expressed on platelets, monocytes, macrophages, and several other cell types that was recently demonstrated to be involved in platelet activation in response to oxidized phospholipids, including oxidized LDL. Although the role of CD36 in other vascular cells has not been well defined, previous studies have demonstrated that cd36-knockout (cd36 -/-) mice have prolonged thrombosis times after vascular injury, which can be protective in the state of hyperlipidemia. Here, we found significantly less ROS in the vessel walls of cd36 -/-mice compared with WT after chemically induced arterial injury, suggesting that CD36 may contribute to ROS generation in the VSMCs themselves. Gene expression analysis revealed that the antioxidant enzymes peroxiredoxin-2 (Prdx2) and heme oxygenase-1 were upregulated in cd36 -/-VSMCs. Molecular dissection of the pathway in isolated mouse VSMCs revealed CD36 ligand-dependent induction of Fyn phosphorylation, with subsequent phosphorylation and degradation of the redox-sensitive transcription factor Nrf2. Chromatin immunoprecipitation experiments further showed that Nrf2 directly occupied the Prdx2 promoter. The importance of this pathway was evidenced by increased ROS generation in prdx2 -/-mice and decreased thrombosis times in both prdx2 -/-and nrf2 -/-mice after vascular injury. These data suggest that CD36-mediated downregulation of antioxidant systems in VSMCs may contribute to its prothrombotic, proinflammatory, and atherogenic effects. Introduction CD36, a class B scavenger receptor, is an 88-kDa membrane glycoprotein expressed on platelets, monocytes, macrophages, and several other cell types (1). It is a multifunctional receptor with independent capacity to bind 3 major classes of ligands: modified phospholipids, long-chain fatty acids, and proteins containing thrombospondin structural homology domains. Although CD36 was first identified on platelets, its role in platelet function remained undefined until recently, when our group showed that CD36 promotes platelet activation in response to oxidized phospholipids, including oxidized LDL (oxLDL) (2). We found that genetic deletion of CD36 in mice protected them from the prothrombotic state associated with hyperlipidemia (2) and oxidant stress and also significantly prolonged thrombotic occlusion times after vascular injury induced by ferric chloride (FeCl 3 ) (3). The mechanisms underlying this phenotype remain incompletely understood, but the antithrombotic effects of CD36 deficiency were dependent on the dose of FeCl 3 used to induce injury (3) and platelet transfusion studies revealed that they were in part platelet dependent. Furthermore, CD36-mediated signaling through specific Src family kinases and MAPKs was shown to promote platelet activation after vascular injury (4). The endogenous CD36 ligands generated during FeCl 3 -induced injury include endothelial cellderived microparticles (EMPs), which we showed bind specifically to platelet CD36 and enhance platelet reactivity (3).

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“…PPAR-γ is an anti-inflammatory transcriptional factor [11]. As shown in figure 2a, we found that PPAR-γ activity was significantly decreased in the DES group (p = 0.007; fig.…”

Section: Resultsmentioning

confidence: 69%

Drug-Eluting Stent, but Not Bare Metal Stent, Accentuates the Systematic Inflammatory Response in Patients

Liu

Zhuo²,

Liu³

et al. 2014

Cardiology

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Objective: The systematic pro-inflammatory responses after percutaneous coronary intervention with drug-eluting stents (DES) remain poorly defined. Therefore, we compared the systematic pro-inflammatory state of circulating mononuclear cells (MNCs) between DES and bare metal stent (BMS) implantation. Methods: Patients with indications for treatment with stents were randomized in a 1:1 ratio to placement of DES or BMS. The primary endpoint was a change of pro-inflammatory state at 12 weeks post-procedure. Results: Thirty-six consecutive patients received DES or BMS. At 12 weeks after stent implantation, the lipid profile and high-sensitivity C-reactive protein (hs-CRP) improved significantly in both groups. The mRNA levels and plasma concentrations of interleukin-6, tumor necrosis factor-a and matrix metalloproteinase-9 were significantly elevated in the DES group, which was not observed in the BMS group. An increase in NF-γB binding activity and a decrease in PPAR-γ expression in MNCs were observed in the DES group, along with increases in IγB phosphorylation and p50 expression. However, similar changes were not observed in the BMS group. Conclusions: Systematic inflammatory responses were accentuated after the patients were treated percutaneously with DES, despite their improved lipid profile and hs-CRP. These data may provide fundamental information for optimizing therapeutic strategy in the era of DES.

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High glucose promotes intracellular lipid accumulation in vascular smooth muscle cells by impairing cholesterol influx and efflux balance

Cited by 66 publications

References 37 publications

17β-estradiol promotes cholesterol efflux from vascular smooth muscle cells through a liver X receptor α-dependent pathway

17β-estradiol promotes cholesterol efflux from vascular smooth muscle cells through a liver X receptor α-dependent pathway

CD36 participates in a signaling pathway that regulates ROS formation in murine VSMCs

Drug-Eluting Stent, but Not Bare Metal Stent, Accentuates the Systematic Inflammatory Response in Patients

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