In:
American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 293, No. 3 ( 2007-09), p. E681-E689
Abstract:
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, [ 3 H]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 (Ser 437 , +159 ± 43%; Thr 308 , +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 G 1 /S transition due to an increased ratio of cyclin E/p27 Kip (4.2-fold), upregulation of p21 WAF-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.
Type of Medium:
Online Resource
ISSN:
0193-1849
,
1522-1555
DOI:
10.1152/ajpendo.00584.2006
Language:
English
Publisher:
American Physiological Society
Publication Date:
2007
detail.hit.zdb_id:
1477331-4
SSG:
12
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