Open AccessInhibition of Vascular c‐Jun N‐Terminal Kinase 2 Improves Obesity‐Induced Endothelial Dysfunction After Roux‐en‐Y Gastric Bypass
Author(s) -
Doytcheva Petia,
Bächler Thomas,
Tarasco Erika,
Marzolla Vincenzo,
Engeli Michael,
Pellegrini Giovanni,
Stivala Simona,
Rohrer Lucia,
Tona Francesco,
Camici Giovanni G.,
Vanhoutte Paul M.,
Matter Christian M.,
Lutz Thomas A.,
Lüscher Thomas F.,
Osto Elena
Publication year - 2017
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.117.006441
Subject(s) - medicine , endothelial dysfunction , phosphorylation , endocrinology , insulin resistance , kinase , glucagon like peptide 1 , c jun , insulin , type 2 diabetes , pharmacology , diabetes mellitus , biology , microbiology and biotechnology , biochemistry , gene , transcription factor
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 JNK 1 or JNK 2 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‐ JNK i‐1 (20 mg/kg per day subcutaneous). JNK peptide inhibitor D‐ JNK i‐1 treatment improved endothelial vasorelaxation in response to insulin and glucagon‐like peptide‐1, as observed after RYGB . Obesity increased aortic phosphorylation of JNK 2, but not of JNK 1. RYGB and JNK peptide inhibitor D‐ JNK i‐1 treatment blunted aortic JNK 2 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 JNK 2 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 JNK 2 against the severe cardiovascular disease associated with obesity.