Elena Osto1, Petia Doytcheva2, Caroline Corteville2, Marco Bueter2, Claudia Dörig2, Simona Stivala2, Helena Buhmann2, Sophie Colin2, Lucia Rohrer2, Reda Hasballa2, Anne Tailleux2, Christian Wolfrum2, Francesco Tona2, Jasmin Manz2, Diana Vetter2, Kerstin Spliethoff2, Paul M Vanhoutte2, Ulf Landmesser2, Francois Pattou2, Bart Staels2, Christian M Matter2, Thomas A Lutz2, Thomas F Lüscher2. 1. From Centre for Molecular Cardiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Switzerland (E.O., P.D., S.S., J.M., U.L., C.M.M., T.F.L.); Institute of Veterinary Physiology, University of Zurich, Switzerland (P.D., C.C., C.D., H.B., K.S., T.A.L.); Department of Surgery (M.B., D.V.) and Institute of Clinical Chemistry (L.R., R.H.), University Hospital Zurich, Switzerland; Université Lille 2, INSERM UMR1011, EGID, Institut Pasteur de Lille, France (S.C., A.T., B.S.); Department of Health Sciences and Technology, ETH Zurich, Switzerland (C.W.); Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Italy (F.T.); State Key Laboratory for Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, University of Hong Kong, SAR (P.M.V.); and Department of Endocrine Surgery, Lille University Hospital, France (F.P.). elena.osto@uzh.ch. 2. From Centre for Molecular Cardiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Switzerland (E.O., P.D., S.S., J.M., U.L., C.M.M., T.F.L.); Institute of Veterinary Physiology, University of Zurich, Switzerland (P.D., C.C., C.D., H.B., K.S., T.A.L.); Department of Surgery (M.B., D.V.) and Institute of Clinical Chemistry (L.R., R.H.), University Hospital Zurich, Switzerland; Université Lille 2, INSERM UMR1011, EGID, Institut Pasteur de Lille, France (S.C., A.T., B.S.); Department of Health Sciences and Technology, ETH Zurich, Switzerland (C.W.); Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Italy (F.T.); State Key Laboratory for Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, University of Hong Kong, SAR (P.M.V.); and Department of Endocrine Surgery, Lille University Hospital, France (F.P.).
Abstract
BACKGROUND: Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight loss-independent manner. The present study investigated in rats and patients whether obesity-induced endothelial and high-density lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1-dependent mechanism. METHODS AND RESULTS: Eight days after RYGB in diet-induced obese rats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin9-39 (10 μg·kg(-1)·h(-1)). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDL-mediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB. CONCLUSIONS: RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1-mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity.
BACKGROUND: Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obesepatients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight loss-independent manner. The present study investigated in rats and patients whether obesity-induced endothelial and high-density lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1-dependent mechanism. METHODS AND RESULTS: Eight days after RYGB in diet-induced obeserats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin9-39 (10 μg·kg(-1)·h(-1)). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDL-mediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB. CONCLUSIONS: RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1-mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity.
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