Rapid and Body Weight–Independent Improvement of Endothelial and High-Density Lipoprotein Function After Roux-en-Y Gastric Bypass
Elena OstoFrom 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.CPetia DoytchevaFrom 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.CCaroline CortevilleFrom 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.CMarco BueterFrom 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.CClaudia DörigFrom 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.CSimona StivalaFrom 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.CHelena BuhmannFrom 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.CSophie ColinFrom 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.CLucia RohrerFrom 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.CReda HasballaFrom 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.CAnne TailleuxFrom 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.CChristian WolfrumUniversity of Hong KongFrancesco TonaFrom 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.CJasmin ManzFrom 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.CDiana VetterUniversity of Hong KongKerstin SpliethoffFrom 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.CPaul M. VanhoutteFrom 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.CUlf LandmesserUniversity of Hong KongFrançois PattouFrom 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.CBart StaelsFrom 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.CChristian M. MatterUniversity of Hong KongThomas A. LutzFrom 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.CThomas F. LüscherFrom 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
2015en
ABI
Annotatsiya
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.
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