Abstract
Endothelial senescence plays crucial roles in diabetic vascular complication. Recent evidence indicated that transient hyperglycaemia could potentiate persistent diabetic vascular complications, a phenomenon known as “metabolic memory.” Although SIRT1 has been demonstrated to mediate high glucose-induced endothelial senescence, whether and how “metabolic memory” would affect endothelial senescence through SIRT1 signaling remains largely unknown. In this study, we investigated the involvement of SIRT1 axis as well as the protective effects of resveratrol (RSV) and metformin (MET), two potent SIRT1 activators, during the occurrence of “metabolic memory” of cellular senescence (senescent “memory”). Human umbilical vascular endothelial cells (HUVECs) were cultured in either normal glucose (NG)/high glucose (HG) media for 6 days, or 3 days of HG followed by 3 days of NG (HN), with or without RSV or MET treatment. It was shown that HN incubation triggered persistent downregulation of deacetylase SIRT1 and upregulation of acetyltransferase p300, leading to sustained hyperacetylation (at K382) and activation of p53, and subsequent p53/p21-mediated senescent “memory.” In contrast, senescent “memory” was abrogated by overexpression of SIRT1 or knockdown of p300. Interestingly, we found that SIRT1 and p300 could regulate each other in response to HN stimulation, suggesting that a delicate balance between acetyltransferases and deacetylases may be particularly important for sustained acetylation and activation of non-histone proteins (such as p53), and eventually the occurrence of “metabolic memory.” Furthermore, we found that RSV or MET treatment prevented senescent “memory” by modulating SIRT1/p300/p53/p21 pathway. Notably, early and continuous treatment of MET, but not RSV, was particularly important for preventing senescent “memory.” In conclusion, short-term high glucose stimulation could induce sustained endothelial senescence via SIRT1/p300/p53/p21 pathway. RVS or MET treatment could enhance SIRT1-mediated signaling and thus protect against senescent “memory” independent of their glucose lowering mechanisms. Therefore, they may serve as promising therapeutic drugs against the development of “metabolic memory.”
Highlights
The prevalence of diabetes has been steadily rising in recent decades
To explore whether transient high glucose could induce persistent endothelial senescence, a cellular model of senescent “memory”, Human umbilical vascular endothelial cells (HUVECs) were subcultured in three different types of endothelial cell (EC) media: normal glucose (NG; 5 mM, 6 days), high glucose (HG; 30 mM, 6 days), or high glucose followed by normal glucose media (HN; 3 days of HG + 3 days of NG)
The discovery of “metabolic memory” in both T1D and T2D patients strongly suggested that lowering blood glucose to normal level as early as the onset of diabetes may significantly delay the occurrence of diabetic vascular complications
Summary
The prevalence of diabetes has been steadily rising in recent decades. Owing to its high prevalence, diabetic vascular complications have become a global health burden. One of the major contributors in the development of diabetes-associated cardiovascular diseases is endothelial senescence, a permanent arrest of cellular growth and proliferation. High blood glucose in diabetes patients has been demonstrated to be a crucial factor accelerating the progression of endothelial senescence. Substantial evidence indicated that hyperglycaemia-induced production of reactive oxygen species (ROS) may promote telomere shortening and DNA damage, trigger a p53-dependent damage response, impair the repair capacity of endothelial lining, lead to a more pro-inflammatory, pro-atherosclerotic, and pro-thrombotic phenotype, and accelerate the development of diabetic vascular complications [2,3,4,5]
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