R-(+)-α-lipoic acid inhibits endothelial cell apoptosis and proliferation: involvement of Akt and retinoblastoma protein/E2F-1
| Autor: | Kathrin Muth, Werner Waldhäusl, Nicole Huttary, Sabina Baumgartner-Parzer, Michaela Artwohl, Thomas Hölzenbein, Angelika Freudenthaler, Karin Kosulin, Leopold Schmetterer, Georg Rainer, Rainer de Martin |
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| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_specialty
Programmed cell death Physiology Endocrinology Diabetes and Metabolism Apoptosis Biology chemistry.chemical_compound Physiology (medical) Internal medicine medicine Humans Endothelial dysfunction Protein kinase B Cells Cultured Cell Proliferation Dose-Response Relationship Drug Thioctic Acid Cell growth Retinoblastoma protein Endothelial Cells medicine.disease Cell biology Endothelial stem cell Lipoic acid Endocrinology chemistry Cancer research biology.protein E2F1 Transcription Factor Signal Transduction |
| Zdroj: | American Journal of Physiology-Endocrinology and Metabolism. 293:E681-E689 |
| ISSN: | 1522-1555 0193-1849 |
| Popis: | Lipoic acid was recently demonstrated to improve endothelial dysfunction or retinopathy not only in rats but also in diabetic patients. We tested the hypothesis that R-(+)-α-lipoic acid (LA) directly affects human endothelial cell (EC) function (e.g., apoptosis, proliferation, and protein expression), independent of the cells' vascular origin. Macrovascular EC (macEC), isolated from umbilical (HUVEC) and adult saphenous veins and from aortae, as well as microvascular EC (micEC) from retinae, skin, and uterus, were exposed to LA (1 μmol/l–1 mmol/l) with/without different stimuli (high glucose, TNF-α, VEGF, wortmannin, LY-294002). Apoptosis, proliferation, cell cycle distribution, and protein expression were determined by DNA fragmentation assays, [3H]thymidine incorporation, FACS, and Western blot analyses, respectively. In macro- and microvascular EC, LA (1 mmol/l) reduced ( P < 0.05) basal (macEC, −36 ± 4%; micEC, −46 ± 6%) and stimulus-induced (TNF-α: macEC, −75 ± 11%; micEC, −68 ± 13%) apoptosis. In HUVEC, inhibition of apoptosis by LA (500 μmol/l) was paralleled by reduction of NF-κB. LA's antiapoptotic activity was reduced by PI 3-kinase inhibitors (wortmannin, LY-294002), being in line with LA-induced Akt phosphorylation (Ser437, +159 ± 43%; Thr308, +98 ± 25%; P < 0.01). LA (500 μmol/l) inhibited ( P < 0.001) proliferation of macEC (−29 ± 3%) and micEC (−29 ± 3%) by arresting the cells at the G1/S transition due to an increased ratio of cyclin E/p27Kip (4.2-fold), upregulation of p21WAF-1/Cip1 (+104 ± 21%), and reduction of cyclin A (−32 ± 11%), of hyperphosphorylated retinoblastoma protein (macEC: −51 ± 7%; micEC: −50 ± 15%), and of E2F-1 (macEC: −48 ± 3%; micEC: −31 ± 10%). LA's ability to inhibit apoptosis and proliferation of ECs could beneficially affect endothelial dysfunction, which precedes manifestation of late diabetic vascular complications. |
| Databáze: | OpenAIRE |
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