In:
Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. suppl_1 ( 2014-05)
Kurzfassung:
Anti-diabetic activities of HDL apolipoprotein(apo)s have been described, complementing ability to reduce atherosclerosis. These effects have been attributed, in part, to apos stimulating cholesterol efflux from cells via ABCA1. This suggests apo mimetic peptides that promote ABCA1 cholesterol efflux may be useful to combat diabetes and its cardiovascular complications. Two such peptides (CS6253 and T6991-2) with optimized safety features (NOAEL = 500 mg/kg) and little TG elevating effects have been designed by us through structure-activity studies of a prototypic ABCA1 ligand peptide, ATI-5261, derived from the C-terminal (CT) domain of apoE. Glucose lowering and insulin sensitizing effects of these new peptides were presently evaluated in mouse models of obesity and diabetes. Peptides CS6253 and T6991-2 stimulated cholesterol efflux from macrophages via ABCA1 with high potency similar to the native apoE CT domain (Km= 0.33±0.14, 0.24±02, 0.21±0.02 μM). Administration of CS6253 at a dose of 30 mg/kg (SC) on alternate days for 6 weeks reduced atherosclerosis by 32% in apoE deficient mice fed high-fat, Western diet for 14 weeks (15±2 vs. 22±4% plaque lesions, CS6253 vs. control, p 〈 0.01). T6991-2 administered (SC) at a dose of 10 mg/kg for 6 weeks in chow-fed ob/ob mice showed little effect on steady-state plasma glucose levels vs. controls (126±22 vs. 135±11 mg/dl, respectively); however, the levels of glucose were greatly attenuated with peptide treatment vs. controls in response to GTT (1.8±0.5 vs. 2.8±0.4 fold increases in plasma glucose at 60 min, respectively, p 〈 0.01). Treatment of C57BL/6J mice fed high-fat diet (HFD) with T6991-2 (6 weeks, 30 mg/kg) also enhanced insulin sensitivity by 2.2±0.7 fold vs. controls (55±17 vs. 25±5% reduction in basal glucose levels, respectively, at 15 minutes post insulin, 0.75 Units/kg, p 〈 0.01). The favorable anti-diabetic effects of T6991-2 were not due to changes in total body weight or β-cell function (i.e. unchanged plasma C-peptide levels). Our data indicate that single amphipathic α-helix peptides derived from apoE CT domain are sufficient to confer potent cellular cholesterol efflux and anti-diabetic activities, with therapeutic potential for diabetes and cardiovascular disease.
Materialart:
Online-Ressource
ISSN:
1079-5642
,
1524-4636
DOI:
10.1161/atvb.34.suppl_1.65
Sprache:
Englisch
Verlag:
Ovid Technologies (Wolters Kluwer Health)
Publikationsdatum:
2014
ZDB Id:
1494427-3
