Hyperglycemia Promotes Endothelial Cell Senescence through AQR/PLAU Signaling Axis

Abstract

Hyperglycemia is reported to accelerate endothelial cell senescence that contributes to diabetic complications. The underlying mechanism, however, remains elusive. We previously demonstrated AQR as a susceptibility gene for type 2 diabetes mellitus (T2DM) and showed that it was increased in multiple tissues in models with T2DM or metabolic syndrome. This study aimed to investigate the role of AQR in hyperglycemia-induced senescence and its underlying mechanism. Here, we retrieved several datasets of the aging models and found the expression of AQR was increased by high glucose and by aging across species, including C. elegans (whole-body), rat (cardiac tissues), and monkey (blood). we validated the increased AQR expression in senescent human umbilical vein endothelial cells (HUVECs). When overexpressed, AQR promoted the endothelial cell senescence, confirmed by an increased number of cells stained with senescence-associated beta-galactosidase and upregulation of CDKN1A (P21) as well as the prohibited cellular colony formation and G2/M phase arrest. To explore the mechanism by which AQR regulated the cellular senescence, transcriptomic analyses of HUVECs with the overexpression and knockdown of the AQR were performed. We identified 52 co-expressed genes that were enriched, in the terms of plasminogen activation, innate immunity, immunity, and antiviral defense. Among co-expressed genes, PLAU was selected to evaluate its contribution to senescence for its highest strength in the enrichment of the biological process. We demonstrated that the knockdown of PLAU rescued senescence-related phenotypes, endothelial cell activation, and inflammation in models induced by AQR or TNF-α. These findings, for the first time, indicate that AQR/PLAU is a critical signaling axis in the modulation of endothelial cell senescence, revealing a novel link between hyperglycemia and vascular dysfunction. The study may have implications in the prevention of premature vascular aging associated with T2DM.

Protection of diabetes in aortic abdominal aneurysm: Are antidiabetics the real effectors?

“…Hyperglycemia, a common risk factor for T1DM and T2DM, drives inflammation and reactive oxygen species (ROS) production, impairing endothelial cell and VSMC function ( 48 – 52 ). In addition, hyperglycemia accelerates senescence in endothelial cells ( 52 , 53 ), VSMCs ( 54 , 55 ), endothelial progenitor cells ( 56 ) and mesenchymal stem cells ( 57 ), which contributes to vascular dysfunction. Hyperglycemia induces changes in VSMC responses to vascular injury ( 55 ), which have been described to be mediated, at least in part, by β3 integrin signaling ( 55 ) and by suppression of insulin receptor substrate-1-mediated p53/KLF4 complex stabilization ( 58 ).…”

Role of Senescent Cells in Cutaneous Wound Healing

“…Hyperglycemia also promotes senescence and drives various senescence responses including the SASP [ 45 ]. For example, hyperglycemia promotes the expression of the AQR gene which induces senescence in endothelial cells [ 51 ]. As mentioned, chronic wounds are highly susceptible to developing bacterial biofilms and pathogenic infections that can lead to sepsis and death [ 6 ].…”

“…Senescent cells vary by type, distribution, SASP production, and elicit varying phenotypes depending on wound chronicity [ 42 , 46 , 52 , 53 , 54 , 55 ]. Cellular senescence may participate in physiologic healing in acute contexts while inhibiting overall wound closure in a chronic setting [ 42 , 50 , 51 , 52 , 54 , 56 , 57 , 58 , 59 ].…”

A review of pathobiological mechanisms and potential application of medicinal plants for vascular aging: focus on endothelial cell senescence

“…24,31 These senescent ECs show important phenotypes such as reduced endothelial nitric oxide synthase activity, enhanced oxidative stress, and the expression of senescence-associated secretory phenotype (SASP).³² High glucose conditions may accelerate a senescence-like state in EC. 33 This raised the question of whether the senescent EC solely may induce ageassociated metabolic dysfunction. Moreover, the senescence in EC leads to systemic insulin resistance.…”