The vicious cycle between transglutaminase 2 and reactive oxygen species in hyperglycemic memory–induced endothelial dysfunction

Abstract

Clinical trials suggested that the vascular system can remember episodes of poor glycemic control through a phenomenon known as hyperglycemic memory (HGM). HGM is associated with long‐term diabetic vascular complications in type 1 and type 2 diabetes, although the molecular mechanism of that association is not clearly understood. We hypothesized that transglutaminase 2 (TGase2) and intracellular reactive oxygen species (ROS) play a key role in HGM‐induced vascular dysfunction. We found that hyperglycemia induced persistent oxidative stress, expression of inflammatory adhesion molecules, and apoptosis in the aortic endothelium of HGM mice whose blood glucose levels had been normalized by insulin supplementation. TGase2 activation and ROS generation were in a vicious cycle in the aortic endothelium of HGM mice and also in human aortic endothelial cells after glucose normalization, which played a key role in the sustained expression of inflammatory adhesion molecules and apoptosis. Our findings suggest that the TGase2‐ROS vicious cycle plays an important role in HGM‐induced endothelial dysfunction.—Lee, J.‐Y., Lee, Y.‐J., Jeon, H.‐Y., Han, E.‐T., Park, W. S., Hong, S.‐H., Kim, Y.‐M., Ha, K.‐S. The vicious cycle between transglutaminase 2 and reactive oxygen species in hyperglycemic memory–induced endothelial dysfunction. FASEB J. 33, 12655–12667 (2019). http://www.fasebj.org

Molecular hydrogen improves type 2 diabetes through inhibiting oxidative stress

“…Hyperglycemia increases the intracellular NADH/NAD + ratio, increasing the risk of electron leakage from NADH or FADH 2 of the electron transport chain, in turn resulting in increased ROS production (4). Additionally, hyperglycemic states can also decrease the expression and activity of enzymes that eliminate ROS, further aggravating oxidative stress (5). Previous studies have demonstrated that excessive ROS accumulation in the mitochondria induced by hyperglycemia can cause damage to the mitochondrial inner membrane.…”

Overexpression of MicroRNA-122 Resists Oxidative Stress-Induced Human Umbilical Vascular Endothelial Cell Injury by Inhibition of p53

“…Endothelial cell injury and dysfunction are major factors contributed to DVT. Previous studies reported that excessive oxidative stress is a common cause of vascular endothelial cell injury [6][7][8]. Moreover, intracellular reactive oxygen species (ROS) can aggravate apoptosis in vascular endothelial cells and decrease antiapoptotic molecule expression [9].…”

Increased Transglutaminase 2 Expression and Activity in Rodent Models of Obesity/Metabolic Syndrome and Aging

“…Appealing theories regarding mechanisms include direct effects of hyperglycemia on fibroblasts to promote their transition to myofibroblasts and subsequent fibrosis; glycation of proteins to form advanced glycation end products (AGEs) that alter the tissue matrices; and increased oxidative stress and inflammation ( Asbun and Villarreal, 2006 ; Ban and Twigg, 2008 ). Studies have demonstrated associations between hyperglycemia ( Skill et al, 2004 ; Bhedi et al, 2020 ), reactive oxygen species ( Lee et al, 2019 ) and inflammatory ( Liu et al, 2019 ) responses and TG2 regulation. Of interest, TG2 -mediated protein serotonylation has been found to be modulated in pancreatic beta cells ( Paulmann et al, 2009 ).…”

“…Highlighting the critical role of TG2 in tissue remodeling, recent studies by Santhanam et al demonstrated that TG2 mediates ventricular ( Oh et al, 2017 ) and aortic ( Steppan et al, 2017 ) contractility, stiffness and function. Furthermore, the events of TG2 alterations are intricately interwoven with influences on transcription factors ( Kumar and Mehta, 2012 ; Brown, 2013 ; Penumatsa et al, 2014 ), inflammation ( Liu et al, 2019 ), oxidative stress ( Lee et al, 2019 ), and fibrogenic signaling ( Olsen et al, 2014 ; Penumatsa et al, 2017 ). Thus, TG2 is a potential target for disruption of tissue stiffness that occurs in diseases of the cardiovascular system and lungs.…”