Negative regulation of eNOS-NO signaling by over-SUMOylation of PPARγ contributes to insulin resistance and dysfunction of vascular endothelium in rats.

Abstract

SUMOylation of peroxisome proliferator-activated receptor gamma (PPAR γ) plays important regulatory role in its transcriptional activity. Our recent studies in vitro found that over-SUMOylation of PPARγ, like high glucose and high fat (HG/HF), induced endothelial insulin resistance (IR). However, whether such an event occurs in rats remains unclear. Therefore, our study aimed at investigating whether PPARγ over-SUMOylation could mimic high sucrose/fat diet (HFD) to induce endothelial IR and dysfunction and explored its underlying mechanisms. Normal chow-fed rats were intravenously infected with adenoviruses carrying the wild type cDNAs encoding PPARγ, SUMO1 and PIAS1 (protein inhibitor of activated STAT1). HFD-fed rats were regarded as a positive control. Body physical and biochemical parameters, glucose tolerance and vessel function were detected. The expression and SUMOylation levels of PPARγ were measured by western blotting and co-immunoprecipitation. Our results showed that like HFD, PPARγ over-SUMOylation induced endothelial IR and dysfunction via a negative regulation of eNOS-NO pathway. More importantly, we found that PPARγ over-SUMOylation induced endogenous SUMOylation cascade and exacerbated endothelial IR and dysfunction.The findings will deepen the understanding on PPARγ SUMOylation-regulating insulin signaling network and offer a potential target for prevention and cure of diabetic vascular complications.

• Authors: Wanwan Yuan, Cong Ma, Yumeng Zhou, Mengxi Wang, Guohua Zeng, Qiren Huang
• Journal: Vascular pharmacology (Vascul Pharmacol) 2019 Nov - Dec Vol. 122-123 Pg. 106597 ISSN: 1879-3649 [Electronic] United States
• PMID: 31479752 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Dietary Sugars
• PPAR gamma
• Protein Inhibitors of Activated STAT
• SUMO-1 Protein
• Nitric Oxide
• Nitric Oxide Synthase Type III
• Nos3 protein, rat

Topics

• Animals
• Aorta, Thoracic (enzymology, physiopathology)
• Diet, High-Fat
• Dietary Sugars
• Disease Models, Animal
• Endothelium, Vascular (enzymology, physiopathology)
• Insulin Resistance
• Male
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• PPAR gamma (genetics, metabolism)
• Protein Inhibitors of Activated STAT (genetics, metabolism)
• Rats, Sprague-Dawley
• SUMO-1 Protein (genetics, metabolism)
• Signal Transduction
• Sumoylation
• Vasodilation