Electronegative LDL Impairs Vascular Endothelial Cell Integrity in Diabetes by Disrupting Fibroblast Growth Factor 2 (FGF2) Autoregulation

Lu, Jinchang; Jiang, Wei; Yang, Jun; Chang, Po‐Yuan; Walterscheid, Jeffrey P.; Chen, Hsin Hung; Marcelli, Marco; Tang, Dongdong; Lee, Yuan Teh; Liao, Warren S.L.; Yang, Chao; Chen, Chu Huang

doi:10.2337/db07-1287

Cited by 69 publications

(67 citation statements)

References 38 publications

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“…In addition, L5 induced LOX‐1 expression in the thoracic aortic tissues of C57B6/J mice (Figure 1b; Supporting Information Figure S3D) but failed to induce endothelial senescence in LOX‐1 −/− mice. We previously showed that LOX‐1 serves as a receptor for L5 and mediates its entry into endothelial cells, subsequently inducing apoptosis (Li, Cao, Berndt, Funder, & Liu, 1999; Lu et al., 2008, 2009). Therefore, our results support that LOX‐1 mediates L5‐dependent endothelial senescence.…”

Section: Resultsmentioning

confidence: 99%

“…Vascular senescence may contribute to adverse vascular remodeling before atherosclerosis development (Wang & Bennett, 2012). In the past, we showed that L5 can induce the apoptosis of endothelial cells and cardiomyocytes (Lee et al., 2012; Lu et al., 2008). In the present study, we treated HAECs with a lower concentration of L5 than was previously used, and cellular senescence but not apoptosis was observed.…”

Section: Discussionmentioning

confidence: 99%

“…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). These biochemical properties of L5 have been attributed to its lipid and protein composition, enzymatic activities, and structural features (Ke, Stancel, Bair, & Chen, 2014; Ke 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: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

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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“…23 Our present findings have the important implication that regeneration of endothelial cells and upregulation of endothelial NO synthase expression via Akt signaling activated by vascular endothelial growth factor and other growth factors may not be suppressed by calcium antagonists. 24,25 The number of functional L-type calcium channels significantly decreased in dedifferentiated VSMCs and increased on differentiation. 26 This is consistent with our finding that nifedipine inhibits the dedifferentiation of differentiated VSMCs, thereby suppressing the development and progression of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Nifedipine Inhibits Vascular Smooth Muscle Cell Dedifferentiation via Downregulation of Akt Signaling

Kaimoto

Yasuda²,

Ohishi³

et al. 2010

Hypertension

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Abstract-Calcium is an essential signaling molecule that controls vascular smooth muscle cell (VSMC) contraction, proliferation, and differentiation. Here, we show that the calcium antagonist nifedipine inhibits VSMC dedifferentiation in vitro and in vivo. Differentiated VSMCs cultured on laminin-coated dishes were transferred to laminin-free dishes to induce dedifferentiation. Induction of dedifferentiation resulted in the upregulation of nonmuscle myosin heavy chain expression, a marker of dedifferentiation, and the downregulation of smooth muscle myosin heavy chain expression, a marker of differentiation. Nifedipine significantly inhibited both the induction of these phenotypic changes and upregulation of Akt signaling in these cells. Administration of nifedipine at a low concentration that did not affect blood pressure could inhibit the increase in nonmuscle myosin heavy chain expression and decrease in smooth muscle myosin heavy chain expression in a rat balloon-injury model. Furthermore, nifedipine suppressed neointimal hyperplasia and upregulation of Akt signaling. However, phospho-Akt expression was not suppressed in the regenerating arterial endothelium of the nifedipine-treated rats. The inhibitory effect of the downregulation of Akt signaling by dominant-negative Akt on the induction of VSMC dedifferentiation in the intima was identical to that of nifedipine. In contrast, upregulation of Akt signaling by transfection of the cells with a constitutively active Akt reversed the nifedipine-induced inhibition of VSMC dedifferentiation. In conclusion, nifedipine inhibits VSMC dedifferentiation by suppressing Akt signaling, thereby preventing neointimal thickening. (Hypertension. 2010;56:247-252.)

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“…This highly electronegative LDL has been called L5 because it is the fifth, most electronegative subfraction of LDL isolated by using anion-exchange chromatography (23 ). Plasma concentrations of L5 have been shown to be significantly increased in patients with cardiovascular risks, including smokers and patients with diabetes mellitus and hypercholesterolemia (23)(24)(25), and L5 concentrations are increased to an even greater extent in the plasma of patients with ST-elevation myocardial infarction (26 ).…”

Section: Biologic Interactions Of Crp Lox-1 and Atherogenic Ldlmentioning

confidence: 99%

Interplay between CRP, Atherogenic LDL, and LOX-1 and Its Potential Role in the Pathogenesis of Atherosclerosis

Stancel¹,

Chen

et al. 2016

Clinical Chemistry

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112

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BACKGROUND:Studies have shown that the classic acute-phase protein C-reactive protein (CRP) has proinflammatory effects on vascular cells and may play a causal role in the pathogenesis of coronary artery disease. A growing body of evidence has suggested that interplay between CRP, lectin-like oxidized LDL receptor-1 (LOX-1), and atherogenic LDL may underlie the mechanism of endothelial dysfunction that leads to atherosclerosis.CONTENT: We review the biochemical evidence for an association of CRP, LOX-1, and either oxidized LDL (OxLDL) or electronegative L5 LDL with the pathogenesis of coronary artery disease. Artificially oxidized OxLDL has been studied extensively for its role in atherogenesis, as has electronegative L5 LDL, which is present at increased levels in patients with increased cardiovascular risks. OxLDL and L5 have been shown to stimulate human aortic endothelial cells to produce CRP, indicating that CRP is synthesized locally in the endothelium. The ligand-binding face (B-face) of CRP has been shown to bind the LOX-1 scavenger receptor and increase LOX-1 expression in endothelial cells, thereby promoting the uptake of OxLDL or L5 by LOX-1 into endothelial cells to induce endothelial dysfunction.

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Electronegative LDL Impairs Vascular Endothelial Cell Integrity in Diabetes by Disrupting Fibroblast Growth Factor 2 (FGF2) Autoregulation

Cited by 69 publications

References 38 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

Nifedipine Inhibits Vascular Smooth Muscle Cell Dedifferentiation via Downregulation of Akt Signaling

Interplay between CRP, Atherogenic LDL, and LOX-1 and Its Potential Role in the Pathogenesis of Atherosclerosis

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