Format

Send to

Choose Destination
Am J Physiol Heart Circ Physiol. 2018 Jan 1;314(1):H52-H64. doi: 10.1152/ajpheart.00478.2017. Epub 2017 Sep 29.

TRAF3IP2 mediates high glucose-induced endothelin-1 production as well as endothelin-1-induced inflammation in endothelial cells.

Author information

1
Department of Nutrition and Exercise Physiology, University of Missouri , Columbia, Missouri.
2
Department of Child Health, University of Missouri , Columbia, Missouri.
3
Dalton Cardiovascular Research Center, University of Missouri , Columbia, Missouri.
4
Cardiothoracic Surgery, University of Texas Health Science Center , San Antonio, Texas.
5
Research Service, Harry S. Truman Memorial Veterans' Hospital , Columbia, Missouri.
6
Division of Cardiovascular Medicine, Department of Medicine, University of Missouri , Columbia, Missouri.
7
Research Unit, Fundación para la Investigación Biomédica del Hospital Universitario Prıncipe de Asturias, Alcala de Henares, Madrid , Spain.
8
Instituto Reina Sofıa de Investigación Nefrológica, IRSIN, Madrid , Spain.
9
Department of Medical Pharmacology and Physiology, University of Missouri , Columbia, Missouri.
10
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland.
11
Diabetes and Cardiovascular Center, Department of Medicine, University of Missouri , Columbia, Missouri.
12
Division of Endocrinology, Department of Medicine, University of Missouri , Columbia, Missouri.

Abstract

Hyperglycemia-induced production of endothelin (ET)-1 is a hallmark of endothelial dysfunction in diabetes. Although the detrimental vascular effects of increased ET-1 are well known, the molecular mechanisms regulating endothelial synthesis of ET-1 in the setting of diabetes remain largely unidentified. Here, we show that adapter molecule TRAF3 interacting protein 2 (TRAF3IP2) mediates high glucose-induced ET-1 production in endothelial cells and ET-1-mediated endothelial cell inflammation. Specifically, we found that high glucose upregulated TRAF3IP2 in human aortic endothelial cells, which subsequently led to activation of JNK and IKKβ. shRNA-mediated silencing of TRAF3IP2, JNK1, or IKKβ abrogated high-glucose-induced ET-converting enzyme 1 expression and ET-1 production. Likewise, overexpression of TRAF3IP2, in the absence of high glucose, led to activation of JNK and IKKβ as well as increased ET-1 production. Furthermore, ET-1 transcriptionally upregulated TRAF3IP2, and this upregulation was prevented by pharmacological inhibition of ET-1 receptor B using BQ-788, or inhibition of NADPH oxidase-derived reactive oxygen species using gp91ds-tat and GKT137831. Notably, we found that knockdown of TRAF3IP2 abolished ET-1-induced proinflammatory and adhesion molecule (IL-1β, TNF-α, monocyte chemoattractant protein 1, ICAM-1, VCAM-1, and E-selectin) expression and monocyte adhesion to endothelial cells. Finally, we report that TRAF3IP2 is upregulated and colocalized with CD31, an endothelial marker, in the aorta of diabetic mice. Collectively, findings from the present study identify endothelial TRAF3IP2 as a potential new therapeutic target to suppress ET-1 production and associated vascular complications in diabetes. NEW & NOTEWORTHY This study provides the first evidence that the adapter molecule TRAF3 interacting protein 2 mediates high glucose-induced production of endothelin-1 by endothelial cells as well as endothelin-1-mediated endothelial cell inflammation. The findings presented herein suggest that TRAF3 interacting protein 2 may be an important therapeutic target in diabetic vasculopathy characterized by excess endothelin-1 production.

KEYWORDS:

TRAF3 interacting protein 2; endothelial dysfunction; endothelin-1; hyperglycemia

Comment in

PMID:
28971844
PMCID:
PMC5866390
DOI:
10.1152/ajpheart.00478.2017
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center