O-GlcNAcase overexpression reverses coronary endothelial cell dysfunction in type 1 diabetic mice.
Cardiovascular disease is the primary cause of morbidity and mortality in diabetes, and endothelial dysfunction is commonly seen in these patients. Increased O-linked N-acetylglucosamine (O-GlcNAc) protein modification is one of the central pathogenic features of diabetes. Modification of proteins by O-GlcNAc (O-GlcNAcylation) is regulated by two key enzymes: β-N-acetylglucosaminidase [O-GlcNAcase (OGA)], which catalyzes the reduction of protein O-GlcNAcylation, and O-GlcNAc transferase (OGT), which induces O-GlcNAcylation. However, it is not known whether reducing O-GlcNAcylation can improve endothelial dysfunction in diabetes. To examine the effect of endothelium-specific OGA overexpression on protein O-GlcNAcylation and coronary endothelial function in diabetic mice, we generated tetracycline-inducible, endothelium-specific OGA transgenic mice, and induced OGA by doxycycline administration in streptozotocin-induced type 1 diabetic mice. OGA protein expression was significantly decreased in mouse coronary endothelial cells (MCECs) isolated from diabetic mice compared with control MCECs, whereas OGT protein level was markedly increased. The level of protein O-GlcNAcylation was increased in diabetic compared with control mice, and OGA overexpression significantly decreased the level of protein O-GlcNAcylation in MCECs from diabetic mice. Capillary density in the left ventricle and endothelium-dependent relaxation in coronary arteries were significantly decreased in diabetes, while OGA overexpression increased capillary density to the control level and restored endothelium-dependent relaxation without changing endothelium-independent relaxation. We found that connexin 40 could be the potential target of O-GlcNAcylation that regulates the endothelial functions in diabetes. These data suggest that OGA overexpression in endothelial cells improves endothelial function and may have a beneficial effect on coronary vascular complications in diabetes.
Department of Physiology, University of Arizona, Tucson, Arizona; Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and Department of Medicine, University of California, San Diego, La Jolla, California aymakino@email.arizona.edu.
Ayako
A
Makino
Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and Department of Medicine, University of California, San Diego, La Jolla, California.
Anzhi
A
Dai
Department of Physiology, University of Arizona, Tucson, Arizona; Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and.
Ying
Y
Han
Department of Physiology, University of Arizona, Tucson, Arizona;
Katia D
KD
Youssef
Department of Physiology, University of Arizona, Tucson, Arizona;
Weihua
W
Wang
Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and.
Reshma
R
Donthamsetty
Department of Medicine, University of California, San Diego, La Jolla, California.
Brian T
BT
Scott
Department of Medicine, University of California, San Diego, La Jolla, California.
Hong
H
Wang
Department of Medicine, University of California, San Diego, La Jolla, California.
Wolfgang H
WH
Dillmann
D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D017630:Connexins / Q000378:metabolism; D003324:Coronary Artery Disease / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006031:Glycosylation; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008822:Mice, Transgenic; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D018919:Neovascularization, Physiologic; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D014664:Vasodilation; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000097003:Gap Junction alpha-5 Protein
D000951:Antigens, Neoplasm; D017630:Connexins; D004791:Enzyme Inhibitors; D051548:Histone Acetyltransferases; D006821:Hyaluronoglucosaminidase; D017351:N-Acetylglucosaminyltransferases; D001619:beta-N-Acetylhexosaminidases; D000097003:Gap Junction alpha-5 Protein; C115866:OGA protein, human; C110628:hexosaminidase C
GCA; diabetic vascular complications; endothelial cell dysfunction; endothelium-dependent hyperpolarization; vascular rarefaction