p53 SUMOylation Mediates AOPP-Induced Endothelial Senescence and Apoptosis Evasion

Abstract

The aging of endothelial cells plays a critical role in the development of age-related vascular disease. We established a model of endothelial premature senescence by application of Advanced oxidation protein products (AOPPs) modified bovine serum albumin (AOPP-BSA) in human umbilical vein endothelial cells (HUVECs). This cellular senescence was accompanied with endothelial barrier dysfunction and angiogenesis impairment. It was further revealed that these senescent HUVECs underwent apoptosis evasion and the receptor for advanced glycation endproducts (RAGE) played a role in these processes. The AOPP-induced senescence was regulated by the state of autophagy in HUVECs. We further proved that AOPP-BSA attenuated the autophagy of HUVECs, led to p53 SUMOylation at K386, resulting in endothelial senescence. We also established the animal model of vascular senescence by using ApoE−/− mice fed with high-fat diet plus daily injection of AOPP-BSA to verify the role of p53 SUMOylation in vascular senescence. Combined with intraperitoneal injection of rapamycin, the effect of autophagy on AOPP-induced p53 SUMOylation was also confirmed in vivo. Our data indicates that p53 SUMOylation at K386 plays an important role in AOPP-induced endothelial senescence and apoptosis evasion, suggesting that p53 K386 SUMOylation may serve as a potential therapeutic target in protecting against vascular senescence.

Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced Nav1.5 downregulation and ventricular arrhythmias

“…As stated, PIASy was important in terms of its ability to regulate Cav-3 SUMOylation in response to I/R stimulation. Similar roles for PIASy were reported in regulating specific molecules, including von Hippel-Lindan [35], NF-kappaB essential modulator [36], p53 [37], and Tat-interacting protein 60 [38] in response to different cellular environments.…”

Endothelial senescence in vascular diseases: current understanding and future opportunities in senotherapeutics

“…High levels of glucose or other reducing sugars can introduce advanced glycation end-products (AGEs) into the circulation 72 , and these AGEs can bind to and stimulate ECs, generating ROS 73 . Similarly, the levels of advanced oxidation protein products (AOPPs), which can be increased by AGEs, tend to be high in uremic patients and have been shown to induce senescence in HUVECs 74 . Other substances, such as circulating microparticles (MPs), which are shed from the membrane following a variety of stimuli and are circulated through the bloodstream 75 , can lead to endothelial dysfunction by mediating NO and ROS production 76 , 77 .…”

A potential role of autophagy-mediated vascular senescence in the pathophysiology of HFpEF

“…Advanced oxidation protein products (AOPPs) result from cell oxidative stress and are accumulated and increased in patients with vascular disease and aging ( 153 ). In HUVECs, AOPPs induced senescence, increasing the expression of p21, p16 and SA β-gal activity, along with an impairment in autophagic flux ( 154 ). The effects of AOPPs were also evaluated in a model of ApoE -/- mice fed with a HFD, which showed an increase in senescence molecular markers in aortic tissue ( 154 ).…”

“…In HUVECs, AOPPs induced senescence, increasing the expression of p21, p16 and SA β-gal activity, along with an impairment in autophagic flux ( 154 ). The effects of AOPPs were also evaluated in a model of ApoE -/- mice fed with a HFD, which showed an increase in senescence molecular markers in aortic tissue ( 154 ). Interestingly, it has been reported that autophagy reduces apoptosis and senescence induced by high glucose concentrations in human coronary artery ECs ( 155 ).…”

“…ROS and inflammation have also been described as characteristic features of vascular aging, and the resulting vascular remodeling and dysfunction ( 172 ). It has been shown that ROS induces senescence in both VSMCs and ECs ( 92 , 93 , 154 ), and that this leads to unpaired vasodilation and vascular stiffness, both of which have been observed in HFpEF patients ( 17 , 37 – 42 ). As with aging, during hypertension, another important comorbidity of HFpEF, vascular senescence is observed ( 88 ).…”