Unsaturated fatty acids liberated from VLDL cause apoptosis in endothelial cells

Reinbold, Michael; Hufnagel, B.; Kewitz, Tobias; Klumpp, Susanne; Krieglstein, Josef

doi:10.1002/mnfr.200700321

Cited by 18 publications

(7 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…V5 was internalized more rapidly than V1–V4, suggesting a high affinity between V5 components and the binding sites of the VLDL receptor. Once internalized, the lipolysis products of VLDL may either initiate physiologic reactions, such as the activation of peroxisome proliferator–activated receptor-α (21), or participate in pathologic activities, such as the induction of apoptosis (22). In preliminary experiments in which we extracted total lipids from V1–V5 by the Bligh-Dyer method (23), we found that V5 lipids induced more extensive endothelial cell apoptosis than did V1–V4 lipids (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Effects of Electronegative VLDL on Endothelium Damage in Metabolic Syndrome

Chen

Lu²,

Chen³

et al. 2012

Diabetes Care

View full text Add to dashboard Cite

OBJECTIVEBiochemical heterogeneity governs functional disparities among lipoproteins. We examined charge-defined VLDL subfractions in metabolic syndrome (MetS) to determine whether their increased electronegativity is associated with increased cytotoxicity and whether high concentrations of highly electronegative subfractions render VLDL harmful to the vascular endothelium.RESEARCH DESIGN AND METHODSPlasma VLDL of normal individuals (control subjects) (n = 13) and of those with MetS (n = 13) was resolved into subfractions with increasing negative charge (V1–V5) by anion-exchange chromatography. Human aortic endothelial cells were treated with V1–V5 or unfractionated VLDL.RESULTSCompared with the control subjects, individuals with MetS had a significantly higher percentage of V5 VLDL (V5/VLDL%) (34 ± 20 vs. 39 ± 11%, respectively; P < 0.05) and plasma V5 concentration ([V5]) (5.5 ± 4.4 vs. 15.2 ± 8.5 mg/dL, respectively; P < 0.001). Apolipoprotein (apo)B100 levels decreased and apoC levels increased from V1 to V5, indicating that V5 is apoC-rich VLDL. Regression analyses of all 26 individuals showed that [V5] was positively correlated with total cholesterol (P = 0.016), triglyceride (P < 0.000001), and V5/VLDL% (P = 0.002). Fasting plasma glucose, but not waist circumference, exhibited a positive trend (P = 0.058); plasma HDL cholesterol exhibited a weak inverse trend (P = 0.138). V5 (10 μg/mL) induced apoptosis in ~50% of endothelial cells in 24 h. V5 was the most rapidly (<15 min) internalized subfraction and induced the production of reactive oxygen species (ROS) in endothelial cells after 20 min. Unfractionated MetS VLDL, but not control VLDL, also induced ROS production and endothelial cell apoptosis.CONCLUSIONSIn populations with increased risk of diabetes, the vascular endothelium is constantly exposed to VLDL that contains a high proportion of V5. The potential impact of V5-rich VLDL warrants further investigation.

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of Electronegative VLDL on Endothelium Damage in Metabolic Syndrome

Chen

Lu²,

Chen³

et al. 2012

Diabetes Care

View full text Add to dashboard Cite

show abstract

“…In a first approach we treated HUVECs with lipoproteins and initiated apoptosis when lipoproteins were cleaved by LPL [3]. We could also show that a physiological amount of LPL, produced by macrophages, was capable of liberating MUFAs at a concentration high enough to cause apoptosis in endothelial cells [6]. These results fostered the idea that apoptosis of endothelial cells caused by MUFAs could represent an initial step in the development of atherosclerosis.…”

Section: Discussionmentioning

confidence: 69%

“…These cells are exposed to high plasma levels of free fatty acids due to the fact that lipoprotein lipase (LPL) hydrolyzes triglycerides from lipoproteins [8]. Accordingly, we treated cultured endothelial cells and macrophages by MUFAs liberated from VLDL and observed an increase in apoptosis [6]. High levels of the plasma lipoproteins LDL and VLDL are among the pathophysiologic stimuli that induce endothelial apoptosis [9], [10] leading to endothelial dysfunction [11], [12].…”

Section: Introductionmentioning

confidence: 99%

Damage of Guinea Pig Heart and Arteries by a Trioleate-Enriched Diet and of Cultured Cardiomyocytes by Oleic Acid

Krieglstein

Kewitz

Kirchhefer³

et al. 2010

PLoS ONE

Self Cite

View full text Add to dashboard Cite

BackgroundMono-unsaturated fatty acids (MUFAs) like oleic acid have been shown to cause apoptosis of cultured endothelial cells by activating protein phosphatase type 2C α and β (PP2C). The question arises whether damage of endothelial or other cells could be observed in intact animals fed with a trioleate-enriched diet.Methodology/Principal FindingsDunkin-Hartley guinea pigs were fed with a trioleate-enriched diet for 5 months. Advanced atherosclerotic changes of the aorta and the coronary arteries could not be seen but the arteries appeared in a pre-atherosclerotic stage of vascular remodelling. However, the weight and size of the hearts were lower than in controls and the number of apoptotic myocytes increased in the hearts of trioleate-fed animals. To confirm the idea that oleic acid may have caused this apoptosis by activation of PP2C, cultured cardiomyocytes from guinea pigs and mice were treated with various lipids. It was demonstrable that oleic acid dose-dependently caused apoptosis of cardiomyocytes from both species, yet, similar to previous experiments with cultured neurons and endothelial cells, stearic acid, elaidic acid and oleic acid methylester did not. The apoptotic effect caused by oleic acid was diminished when PP2C α and β were downregulated by siRNA showing that PP2C was causally involved in apoptosis caused by oleic acid.Conclusions/SignificanceThe glycerol trioleate diet given to guinea pigs for 5 months did not cause marked atherosclerosis but clearly damaged the hearts by activating PP2C α and β. The diet used with 24% (wt/wt) glycerol trioleate is not comparable to human diets. The detrimental role of MUFAs for guinea pig heart tissue in vivo is shown for the first time. Whether it is true for humans remains to be shown.

show abstract

“…Although oleate can detoxify LC-SFA, that fatty acid was toxic to several cell lines, but less so to LC-SFA. In addition, the mechanisms of oleate-induced cell death differ among cell types [23,34–36] . We also found that oleate had cytotoxic effects at higher concentrations than laurate, and the lipotoxicity of oleate was greater than that of laurate ( Fig.…”

Section: Resultsmentioning

confidence: 99%