Inhibition of vascular c-jun N-terminal kinase 2 improves obesity-induced endothelial dysfunction after roux-en-y gastric bypass
| Autor: | Vincenzo Marzolla, Thomas A. Lutz, Thomas Bächler, Simona Stivala, Christian M. Matter, Elena Osto, Lucia Rohrer, Michael Engeli, Petia Doytcheva, Thomas F. Lüscher, Giovanni Pellegrini, Giovanni G. Camici, Francesco Tona, Paul M. Vanhoutte, Erika Tarasco |
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| Přispěvatelé: | University of Zurich, Osto, Elena |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine obesity Bariatric surgery c-Jun N-terminal kinase Endothelial function Glucagon-like peptide-1 NO 030204 cardiovascular system & hematology Vascular Medicine 0302 clinical medicine Phosphorylation Endothelial dysfunction Original Research 10038 Institute of Clinical Chemistry Kinase c-jun 10081 Institute of Veterinary Physiology Roux-en-Y anastomosis Vasodilation Neuroprotective Agents Cardiovascular Diseases 10076 Center for Integrative Human Physiology Endothelium/Vascular Type/Nitric Oxide 10209 Clinic for Cardiology c‐Jun N‐terminal kinase Cardiology and Cardiovascular Medicine medicine.medical_specialty Injections Subcutaneous Gastric bypass Gastric Bypass 10184 Institute of Veterinary Pathology Pathophysiology 2705 Cardiology and Cardiovascular Medicine 03 medical and health sciences Vascular Biology Internal medicine medicine Animals Mitogen-Activated Protein Kinase 9 Rats Wistar Cardiovascular mortality glucagon‐like peptide‐1 business.industry nutritional and metabolic diseases medicine.disease Obesity Rats Disease Models Animal Oxidative Stress Metabolism 030104 developmental biology Endocrinology 570 Life sciences biology Endothelium Vascular Peptides business Basic Science Research |
| Zdroj: | Journal of the American Heart Association, 6 (11) Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Popis: | Background Roux‐en‐Y gastric bypass (RYGB) reduces obesity‐associated comorbidities and cardiovascular mortality. RYGB improves endothelial dysfunction, reducing c‐Jun N‐terminal kinase (JNK) vascular phosphorylation. JNK activation links obesity with insulin resistance and endothelial dysfunction. Herein, we examined whether JNK1 or JNK2 mediates obesity‐induced endothelial dysfunction and if pharmacological JNK inhibition can mimic RYGB vascular benefits. Methods and Results After 7 weeks of a high‐fat high‐cholesterol diet, obese rats underwent RYGB or sham surgery; sham–operated ad libitum–fed rats received, for 8 days, either the control peptide D‐TAT or the JNK peptide inhibitor D‐JNKi‐1 (20 mg/kg per day subcutaneous). JNK peptide inhibitor D‐JNKi‐1 treatment improved endothelial vasorelaxation in response to insulin and glucagon‐like peptide‐1, as observed after RYGB. Obesity increased aortic phosphorylation of JNK2, but not of JNK1. RYGB and JNK peptide inhibitor D‐JNKi‐1 treatment blunted aortic JNK2 phosphorylation via activation of glucagon‐like peptide‐1–mediated signaling. The inhibitory phosphorylation of insulin receptor substrate‐1 was reduced, whereas the protein kinase B/endothelial NO synthase pathway was increased and oxidative stress was decreased, resulting in improved vascular NO bioavailability. Conclusions Decreased aortic JNK2 phosphorylation after RYGB rapidly improves obesity‐induced endothelial dysfunction. Pharmacological JNK inhibition mimics the endothelial protective effects of RYGB. These findings highlight the therapeutic potential of novel strategies targeting vascular JNK2 against the severe cardiovascular disease associated with obesity. Journal of the American Heart Association, 6 (11) |
| Databáze: | OpenAIRE |
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