Low-Density Lipoprotein in Hypercholesterolemic Human Plasma Induces Vascular Endothelial Cell Apoptosis by Inhibiting Fibroblast Growth Factor 2 Transcription

Chen, Chu Huang; Jiang, Tao; Yang, Jun; Jiang, Wei; Lu, Jinchang; Marathe, Gopal K.; Pownall, Henry J.; Ballantyne, Christie M.; McIntyre, Thomas M.; Henry, Philip D.; Yang, Chao

doi:10.1161/01.cir.0000065220.70220.f7

Cited by 150 publications

(202 citation statements)

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“…Therefore, these findings imply that cellular senescence may mediate endothelial dysfunction and atherogenesis after chronic exposure to a sublethal level of L5. In other studies, we have shown that the concentration of L5 is less than 10 μg/ml in healthy individuals and is 100 μg/ml in patients with acute myocardial infarction (Chan et al., 2013), 20 μg/ml in patients with chronic kidney disease (Chang et al., 2013, 2016), and 100 μg/ml in patients with hypercholesterolemia (Chen et al., 2003). These estimations indicate that the concentration of L5 chosen for our in vitro experiments is the same order of magnitude as the concentration detected in humans, suggesting that our findings may be clinically relevant.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma LDL was isolated from patients with metabolic syndrome using sequential potassium bromide density‐gradient ultra‐centrifugation (density = 1.019–1.063 g/ml) and supplemented with protease inhibitor cocktail, 1% penicillin/streptomycin/neomycin mixture, and 0.5 mM EDTA. Isolated LDL was separated into five subfractions (L1–L5) using an anion‐exchange fast‐protein liquid chromatography system (GE Healthcare, Princeton, NJ, USA), as described previously (Chen et al., 2003). The bioactivity of each batch of L5 was determined by examining its ability to induce endothelial cell apoptosis in 24 hr (Chen et al., 2003).…”

Section: Methodsmentioning

confidence: 99%

“…Isolated LDL was separated into five subfractions (L1–L5) using an anion‐exchange fast‐protein liquid chromatography system (GE Healthcare, Princeton, NJ, USA), as described previously (Chen et al., 2003). The bioactivity of each batch of L5 was determined by examining its ability to induce endothelial cell apoptosis in 24 hr (Chen et al., 2003). The bioactivity of L5 was then used to normalize the concentration of L5 used in subsequent animal and cell experiments.…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, electronegative LDL is a class of naturally occurring lipoproteins that are as atherogenic as oxidized LDL. The most electronegative subfraction of LDL can be obtained using fast‐protein liquid chromatography with anion‐exchange columns to fractionate human LDL into five subfractions with increasing electronegativity, called L1 to L5 (Chen et al., 2003; Ke et al., 2011). The most electronegative subfraction, L5, is the only LDL subfraction that can induce endothelial dysfunction and atherogenic responses in cultivated arteries and cultured vascular cells or impair normal differentiation of endothelial progenitor cells (Chen et al., 2007; Chu et al., 2013; Lu et al., 2008; Stancel et al., 2016).…”

Section: Introductionmentioning

confidence: 99%

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Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo

et al. 2018

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SummaryDysregulation of plasma lipids is associated with age‐related cardiovascular diseases. L5, the most electronegative subfraction of chromatographically resolved low‐density lipoprotein (LDL), induces endothelial dysfunction, whereas the least electronegative subfraction, L1, does not. In this study, we examined the effects of L5 on endothelial senescence and its underlying mechanisms. C57B6/J mice were intravenously injected with L5 or L1 (2 mg kg−1 day−1) from human plasma. After 4 weeks, nuclear γH2AX deposition and senescence‐associated β‐galactosidase staining indicative of DNA damage and premature senescence, respectively, were increased in the aortic endothelium of L5‐treated but not L1‐treated mice. Similar to that, in Syrian hamsters with elevated serum L5 levels induced by a high‐fat diet, nuclear γH2AX deposition and senescence‐associated β‐galactosidase staining were increased in the aortic endothelium. This phenomenon was blocked in the presence of N‐acetyl‐cysteine (free‐radical scavenger) or caffeine (ATM blocker), as well as in lectin‐like oxidized LDL receptor‐1 (LOX‐1) knockout mice. In cultured human aortic endothelial cells, L5 augmented mitochondrial oxygen consumption and mitochondrial free‐radical production, which led to ATM activation, nuclear γH2AX deposition, Chk2 phosphorylation, and TP53 stabilization. L5 also decreased human telomerase reverse transcriptase (hTERT) protein levels and activity. Pharmacologic or genetic manipulation of the reactive oxygen species (ROS)/ATM/Chk2/TP53 pathway efficiently blocked L5‐induced endothelial senescence. In conclusion, L5 may promote mitochondrial free‐radical production and activate the DNA damage response to induce premature vascular endothelial senescence that leads to atherosclerosis. Novel therapeutic strategies that target L5‐induced endothelial senescence may be used to prevent and treat atherosclerotic vascular disease.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo

et al. 2018

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“…10 The biological effects of ox-LDL are likely to depend on the oxidation level of the LDL. 22 Local further oxidation of ox-LDL by ROS produced by chondrocytes could enhance LOX-1 expression in an autocrine or paracrine manner. Indeed, we have demonstrated that TNF-a-and IL-1b-induced ROS production by chondrocytes results in oxidative modification of LDL (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Cyclic tensile stretch load and oxidized low density lipoprotein synergistically induce lectin‐like oxidized ldl receptor‐1 in cultured bovine chondrocytes, resulting in decreased cell viability and proteoglycan synthesis

Akagi

Nishimura

Yoshida

et al. 2006

Journal Orthopaedic Research

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Mechanical stimulation is known to be an essential factor in the regulation of cartilage metabolism. We tested the hypothesis that expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) can be modulated by cyclic tensile stretch load in chondrocytes. Cyclic loading of repeated stretch stress at 10 cycles per minute with 10 kPa of stress for 6 h induced expression of LOX-1 to 2.6 times control in cultured bovine articular chondrocytes, equivalent to the addition of 10 mg/mL oxidized low density lipoprotein (ox-LDL) (2.4 times control). Application of the cyclic load to the chondrocytes along with 10 mg/mL ox-LDL resulted in synergistically increased LOX-1 expression to 6.3 times control. Individual application of cyclic loading and 10 mg/mL ox-LDL significantly suppressed chondrocytes viability (84.6% AE 3.4% and 80.9% AE 3.2% of control at 24 h, respectively; n ¼ 3; p < 0.05) and proteoglycan synthesis [81.0% AE 7.1% and 85.7% AE 5.2% of control at 24 h, respectively; p < 0.05 when compared with 94.6% AE 4.6% for native-LDL (n ¼ 3)]. Cyclic loading and 10 mg/mL ox-LDL synergistically affected cell viability and proteoglycan synthesis, which were significantly suppressed to 45.6% AE 4.9% and 48.7% AE 6.7% of control at 24 h, respectively (n ¼ 3; p < 0.01 when compared with individual application of cyclic loading or 10 mg/ mL ox-LDL). In this study, we demonstrated synergistic effects of cyclic tensile stretch load and ox-LDL on cell viability and proteoglycan synthesis in chondrocytes, which may be mediated through enhanced expression of LOX-1 and which has important implications in the progression of cartilage degeneration in osteoarthritis. ß

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Role of Low‐Density Lipoprotein in Early Vascular Aging Associated With Systemic Lupus Erythematosus

Chan

Liang

Lee

et al. 2020

Arthritis & Rheumatology

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Objective. Patients with systemic lupus erythematosus (SLE) often have atherosclerotic complications at a young age but normal low-density lipoprotein (LDL) levels. This study was undertaken to investigate the role of LDL composition in promoting early vascular aging in SLE patients.Methods. Plasma LDL from 45 SLE patients (SLE-LDL) and from 37 normal healthy controls (N-LDL) was chromatographically divided into 5 subfractions (L1-L5), and the subfraction composition was analyzed. Correlations between subfraction levels and signs of early vascular aging were assessed. Mechanisms of lipid-mediated endothelial dysfunction were explored using in vitro assays and experiments in apoE −/− mice.Results. The L5 percentage was increased 3.4 times in the plasma of SLE patients compared with normal controls. This increased percentage of SLE-L5 was positively correlated with the mean blood pressure (r = 0.27, P = 0.04), carotid intima-media thickness (IMT) (right carotid IMT, r = 0.4, P = 0.004; left carotid IMT, r = 0.36, P = 0.01), pulse wave velocity (r = 0.29, P = 0.04), and blood levels of CD16+ monocytes (r = 0.35, P = 0.004) and CX3CL1 cytokines (r = 0.43, P < 0.001) in SLE patients. Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry analysis revealed that plasma levels of lysophosphatidylcholine (LPC) and platelet-activating factor (PAF) were increased in SLE-LDL and in the SLE-L5 plasma subfraction. Injecting SLE-LDL, SLE-L5, or LPC into young, male apoE −/− mice caused increases in plasma CX3CL1 levels, aortic fatty-streak areas, aortic vascular aging, and macrophage infiltration into the aortic wall, whereas injection of N-LDL or SLE-L1 had negligible effects (n = 3-8 mice per group). In vitro, SLE-L5 lipid extracts induced increases in CX3CR1 and CD16 expression in human monocytes; synthetic PAF and LPC had similar effects. Furthermore, lipid extracts of SLE-LDL and SLE-L5 induced the expression of CX3CL1 and enhanced monocyte-endothelial cell adhesion in assays with bovine aortic endothelial cells.Conclusion. An increase in plasma L5 levels, not total LDL concentration, may promote early vascular aging in SLE patients, leading to premature atherosclerosis.

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Low-Density Lipoprotein in Hypercholesterolemic Human Plasma Induces Vascular Endothelial Cell Apoptosis by Inhibiting Fibroblast Growth Factor 2 Transcription

Abstract: Background-Apoptosis of vascular endothelial cells (ECs

Cited by 150 publications

References 39 publications

Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo

Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo

Cyclic tensile stretch load and oxidized low density lipoprotein synergistically induce lectin‐like oxidized ldl receptor‐1 in cultured bovine chondrocytes, resulting in decreased cell viability and proteoglycan synthesis

Role of Low‐Density Lipoprotein in Early Vascular Aging Associated With Systemic Lupus Erythematosus

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