Abstract 12263: The Role of Glucagon-Like Peptide-1 in the Immediate Improvement of Endothelial-Protective HDL Functions After Roux-en-Y Gastric Bypass in Obese Patients
Introduction: Roux-en-Y gastric bypass (RYGB) reduces body weight (BW) and cardiovascular (CV) mortality in morbidly obese patients (pts). We showed in rats that glucagon-like peptide-1 (GLP-1) contributes to improve endothelial vasorelaxation early after RYGB in a BW loss-independent manner.
Hypothesis: Here, we investigated in rats and patients whether obesity-induced HDL dysfunction improves after RYGB by a GLP-1-dependent mechanism.
Methods: Diet induced obese male Wistar rats undergoing RYGB received vehicle (RYv); sham-operated ad libitum fed rats received vehicle (ALv) or the GLP-1 analog liraglutide (AL-lira; 0.2 mg/kg BID). HDL was isolated after 8 days. In parallel, HDL was also isolated from 28 healthy subjects and 28 morbidly obese pts (BMI >40) before, 14 days and 12 weeks after RYGB. In endothelial cells stimulated with HDL, we assessed nitric oxide (NO) production by DAF-2 fluorescence and endothelial NO synthase (eNOS) protein dimerization. Moreover, we measured paraoxonase-1 (PON-1) antioxidant activity, HDL-stimulated reduction of TNFα-stimulated vascular adhesion molecule-1 (VCAM-1) expression, apoptosis and cholesterol efflux in macrophages, and fasting GLP-1 and total HDL-cholesterol (HDL-C) plasma levels.
Results: GLP-1 increased immediately in RYGB rats and in RYGB pts. Total HDL-C was unchanged. HDL isolated from RYv and AL-lira rats induced higher endothelial NO production and eNOS dimerization than ALv. Endothelial VCAM-1 expression and apoptosis were equally blunted after RYGB and in AL-lira compared to sham ALv, suggesting that elevated GLP-1 improves HDL functions after RYGB. In pts, HDL restored eNOS dimerization and improved endothelial NO release 14 days and 12 weeks after RYGB. Preserved NO bioavailability was paralleled by reduced endothelial apoptosis and VCAM-1 expression, higher PON-1 activity and cholesterol efflux capacity. RYGB restored pts’ HDL functions to the level of healthy subjects, independently of quantitative changes in HDL-C and although our patients were still obese 12 weeks after surgery.
Conclusions: RYGB immediately improves endothelial-protective HDL functions; increased circulating GLP-1 levels seem to be causally involved in these beneficial CV effects after surgery.
Author Disclosures: E. Osto: None. P. Doytcheva: None. H. Buhmann: None. M. Bueter: None. S. Colin: None. L. Rohrer: None. U. Landmesser: None. B. Staels: None. C. Matter: None. T.A. Lutz: None. T.F. Luscher: None.
- © 2014 by American Heart Association, Inc.