Diabetic LDL Triggers Apoptosis in Vascular Endothelial Cells

Artwohl, Michaela; Graier, Wolfgang F.; Roden, Michael; Bischof, Martin; Freudenthaler, Angelika; Waldhäusl, W.; Baumgartner‐Parzer, Sabina

doi:10.2337/diabetes.52.5.1240

Cited by 56 publications

(50 citation statements)

References 50 publications

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“…Even though its extent was limited, it is conceivable that the apoptotic process plays a role in determining a progressive hypocellularity during the late stages of glomerulosclerosis. The proapoptotic effect of glycated LDL, already described in endothelial cells [44], occurs in mesangial cells at a concentration (200 nmol/l) corresponding to~10% of that seen in normal human plasma, thus indicating a very high proapoptotic activity of these particles and the potential clinical relevance of the [45], the prime receptor mediating selective cholesteryl ester uptake from lipoprotein particles. In contrast, native LDL preferentially binds to the classic LDL receptor, and subsequent internalisation leads to uptake of cholesterol and cholesteryl esters.…”

Section: Discussionmentioning

confidence: 76%

Effects of different LDL particles on inflammatory molecules in human mesangial cells

et al. 2008

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Aims/hypothesis Inflammation is a mechanism of glomerular damage in chronic glomerulopathies. LDL may increase the production of inflammatory cytokines in renal tissues. However, the relative role of native, oxidised and glycated LDL in promoting this process has been only partially elucidated. Methods We tested the inflammatory and proapoptotic effects of native, oxidised and glycated LDL in human mesangial cells (HMCs) by measuring levels of IL6, CD40 and macrophage migration inhibitory factor (MIF) genes, MIF protein, release of IL6, soluble CD40, fibronectin and laminin, early and late apoptosis, and extracellular regulated kinases (ERK) 1/2 and c-Jun N-terminal kinase (JNK) activation. Results IL6 and CD40 mRNA were dose-dependently upregulated by all three species; this was closely paralleled by their increased release. MIF mRNA was potently stimulated by modified LDL, as confirmed by immunostaining. Fibronectin and laminin release was stimulated by both oxidised and glycated, but not native, LDL. All LDL species induced some increase in late, but not early, apoptosis, and similarly activated JNK2/3 phosphorylation; in contrast, ERK1/2 phosphorylation was more strongly upregulated by oxidised than either native or glycated LDL.Conclusions In HMCs, the production and release of IL6 and CD40 is stimulated by both native and modified LDL, while MIF is more strongly stimulated by oxidised LDL. Regarding the pattern of mesangial expansion, fibronectin and laminin are upregulated by oxidised and glycated LDL. Apoptosis, if modest, is induced by all species. Intracellular signalling of native and modified LDL involves JNK2/3 and, perhaps more specifically, ERK1/2. Tight control of the lipid profile may be useful in preserving kidney function in patients with metabolic alterations.

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Section: Discussionmentioning

confidence: 76%

Effects of different LDL particles on inflammatory molecules in human mesangial cells

et al. 2008

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“…[ 3 H]thymidine-(1 mCi/ml) labeled endothelial cells, trypsinized and seeded into 24-well culture plates, were exposed to FFAs for 24 h (HUVECs, HAECs, EPCs, HRECs) and for 48 h (HRECs), and experimental as well as intra-individual control cultures (exposed to ethanol) were tested for apoptosis (3,18,20). In brief, the cells were lysed (20 mmol/l Tris-HCl, pH 7.5, 0.4% Triton X-100; 10 min on ice), and fragmented (apoptotic) DNA was separated by centrifugation (3,18,20).…”

Section: Apoptosis Assaysmentioning

confidence: 99%

“…HUVECs, HAECs, and HRECs were isolated, cultured, and identified as described (3,(18)(19)(20) and used in the 1st, 5th, and 2nd subcultures, respectively.…”

Section: Endothelial Cell Culturementioning

confidence: 99%

Different mechanisms of saturated versus polyunsaturated FFA-induced apoptosis in human endothelial cells

Artwohl

Lindenmair

Sexl

et al. 2008

Journal of Lipid Research

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“…Not only could adipose-tissue-derived mediators add to vascular dysfunction 2 but also obesity is associated with a number of comorbidities, including hypertension, hyperlipidemia, systemic inflammation and overt diabetes, all of which could trigger endothelial dysfunction. [2][3][4] Endothelial cell loss through damage/apoptosis induced by atherogenic risk factors 5,6 requires replenishment of endothelial cells in the vessel wall. In this process, two mechanisms are likely to be responsible for postnatal vasculogenesis in physiological and pathophysiological neovascularization: (1) an increased mitotic response and turnover of nearby located endothelial cells and/or (2) reendothelialization by the attachment of endothelial progenitor cells (EPCs).…”

Section: Introductionmentioning

confidence: 99%

Reduction of both number and proliferative activity of human endothelial progenitor cells in obesity

et al. 2010

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Objective: Circulating endothelial progenitor cells (EPCs), responsible for neoangiogenesis and vascular repair, negatively correlate with vascular dysfunction and atherosclerotic risk factors. Because obesity may have a crucial role in the development of endothelial dysfunction, this study evaluated the number and proliferative activity of circulating human EPCs in obese (body mass index (BMI) ¼ 48±9, n ¼ 45) compared with lean (23±2, n ¼ 45) volunteers. Methods: EPCs were quantified after isolation of peripheral blood mononuclear cells (PBMCs) using fluorescence-activated cell sorting analyses. In addition, plated PBMCs developed colony-forming units (CFUs) from which 'outgrowth' endothelial cells (OECs) sprouted and differentiated into mature endothelial cells. Growth rates were monitored by periodical microscopic evaluation. Cell-cycle protein expression was determined by western blot analyses. Results: BMI negatively correlated (Po0.01) with the number of.500) and CD133 þ /KDR þ (r ¼ À0.282) EPCs. Insulin, leptin, HbA 1c , high-sensitivity C-reactive protein and hypertension, as well as diminished high-density lipoprotein and apolipoprotein A1, were not only associated with obesity but also with significantly reduced EPC levels. Applying selective culture conditions, EPC-CFUs differentiated into OECs that proliferated more slowly when derived from obese compared with lean subjects (obese: 19.9 ± 2.2% vs lean: 30.9 ± 3.2% grown area per week, Po0.01). The reduced proliferation was reflected by decreased (Po0.05, n ¼ 24 for each group) expression of cell-cyclepromoting cyclins and E2F-1, by hypophosphorylation of retinoblastoma protein and by increased (Po0.05, n ¼ 24 for each group) expression of the cell-cycle inhibitor p21 WAFÀ1/Cip1 . Conclusions: Reduced numbers of EPCs along with their premature senescence, as shown in this study, could function as early contributors to the development and progression of vascular dysfunction in obesity.

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Diabetic LDL Triggers Apoptosis in Vascular Endothelial Cells

Cited by 56 publications

References 50 publications

Effects of different LDL particles on inflammatory molecules in human mesangial cells

Effects of different LDL particles on inflammatory molecules in human mesangial cells

Different mechanisms of saturated versus polyunsaturated FFA-induced apoptosis in human endothelial cells

Reduction of both number and proliferative activity of human endothelial progenitor cells in obesity

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