Author + information
- Elena Osto,
- Petia Doytcheva,
- Thomas Bächler,
- Thomas Lutz and
- Thomas F. Luscher
Background: Roux-en-Y gastric bypass (RYGB) reduces obesity-associated comorbidities and cardiovascular mortality. We showed in diet-induced obese (DIO) rats that RYGB improves endothelial vasodilatation 8 days after surgery independently from weight loss. The effect was associated with decreased aortic phosphorylation of c-jun N-terminal kinase (JNK), which is a crucial player linking obesity with endothelial dysfunction. Here, we examined if JNK1 or JNK2 mediates obesity-induced endothelial dysfunction and if the beneficial vascular effects after RYGB can be mimicked by pharmacological JNK inhibition.
Methods: After 7 weeks of high-fat high-cholesterol diet, DIO rats underwent RYGB or sham surgery. Sham-operated rats received either control peptide D-TAT or the JNK peptide inhibitor D-JNKi-1 (D-JNK; 20mg/kg/day s.c.) for 8 days after surgery. Cumulative concentration-relaxation curves were obtained in rings of thoracic aorta in response to glucagon like peptide-1 (GLP-1 7-36) amide (10-12 to 10-6mol/L) or insulin (10-12 to 10-5mol/L). Western blot of aortic lysates was performed for JNK, Akt, endothelial nitric oxide (NO) synthase (eNOS) protein phosphorylation. NADPH oxidase activity was measured.
Results: In vivo D-JNK treatment mimicked the improvement in endothelial function seen after RYGB. Obesity increased JNK2, but not JNK1 phosphorylation in the aorta. After RYGB or D-JNK treatment, aortic JNK2 phosphorylation was blunted, as was the inhibitory phosphorylation of insulin receptor substrate-1 (IRS-1), while Akt/eNOS activation was increased. Oxidative stress decreased as shown by decreased aortic NADPH oxidase activity comparably after RYGB and D-JNK treatment, resulting in improved NO bioavailability.
Conclusions: In obese rats, 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 a novel JNK2-dependent mechanism for the cardiovascular benefits of RYGB surgery.
Room 209 C
Saturday, March 18, 2017, 8:25 a.m.-8:35 a.m.
Session Title: Highlighted Original Research: Vascular Medicine and the Year in Review
Abstract Category: 38. Vascular Medicine: Basic
Presentation Number: 905-06
- 2017 American College of Cardiology Foundation