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Inhibition of vascular c-jun N-terminal kinase 2 improves obesity-induced endothelial dysfunction after roux-en-y gastric bypass
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نویسنده
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doytcheva p. ,bächler t. ,tarasco e. ,marzolla v. ,engeli m. ,pellegrini g. ,stivala s. ,rohrer l. ,tona f. ,camici g.g. ,vanhoutte p.m. ,matter c.m. ,lutz t.a. ,lüscher t.f. ,osto e.
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منبع
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journal of the american heart association - 2017 - دوره : 6 - شماره : 11
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چکیده
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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. © 2017 the authors.
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کلیدواژه
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Bariatric surgery; C-Jun N-terminal kinase; Endothelial function; Glucagon-like peptide-1; NO; Obesity
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آدرس
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center for molecular cardiology,university of zurich,switzerland,university heart center,cardiology,university hospital zurich,switzerland,institute of veterinary physiology,vetsuisse faculty university of zurich,switzerland,zurich center for integrative human physiology,university of zurich, Switzerland, department of surgery,cantonal hospital fribourg,fribourg, Switzerland, institute of veterinary physiology,vetsuisse faculty university of zurich,switzerland,zurich center for integrative human physiology,university of zurich, Switzerland, center for molecular cardiology,university of zurich,switzerland,university heart center,cardiology,university hospital zurich,switzerland,laboratory of cardiovascular endocrinology,istituto di ricovero e cura a carattere scientifico san raffaele pisana,rome, Italy, center for molecular cardiology,university of zurich,switzerland,university heart center,cardiology,university hospital zurich, Switzerland, laboratory for animal model pathology,institute for veterinary pathology,vetsuisse faculty university of zurich, Switzerland, center for molecular cardiology,university of zurich,switzerland,university heart center,cardiology,university hospital zurich,switzerland,zurich center for integrative human physiology,university of zurich, Switzerland, institute of clinical chemistry,university hospital zurich,zurich,switzerland,zurich center for integrative human physiology,university of zurich, Switzerland, department of cardiac,thoracic and vascular sciences,university of padova, Italy, center for molecular cardiology,university of zurich,switzerland,university heart center,cardiology,university hospital zurich,switzerland,zurich center for integrative human physiology,university of zurich, Switzerland, state key laboratory for pharmaceutical biotechnologies and department of pharmacology and pharmacy,li ka shing faculty of medicine,the university of hong kong, Hong Kong, center for molecular cardiology,university of zurich,switzerland,university heart center,cardiology,university hospital zurich,switzerland,zurich center for integrative human physiology,university of zurich, Switzerland, center for molecular cardiology,university of zurich,switzerland,university heart center,cardiology,university hospital zurich,switzerland,zurich center for integrative human physiology,university of zurich, Switzerland, zurich center for integrative human physiology,university of zurich, Switzerland, center for molecular cardiology,university of zurich,switzerland,university heart center,cardiology,university hospital zurich,switzerland,zurich center for integrative human physiology,university of zurich,switzerland,laboratory of translational nutrition biology,federal institute of technology zurich (ethz),schwerzenbach, Switzerland
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Authors
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