Giuliani Angelica, Ramini Deborah, Sbriscia Matilde, Crocco Paolina, Tiano Luca, Rippo Maria Rita, Bonfigli Anna Rita, Rose Giuseppina, De Luca Maria, Olivieri Fabiola, Sabbatinelli Jacopo
Istituti Clinici Scientifici Maugeri IRCCS, Cardiac Rehabilitation Unit of Bari Institute, Bari, Italy.
Clinic of Laboratory and Precision Medicine, IRCCS INRCA, Ancona, Italy.
Diabetol Metab Syndr. 2024 Aug 20;16(1):203. doi: 10.1186/s13098-024-01431-8.
Endothelial cellular senescence is emerging as a key mechanism of age-related vascular dysfunction. Disruption of the endothelium glycocalyx and shedding of the syndecan (SDC) ectodomains have been associated with several age-related diseases. Although SDC4 is highly expressed in endothelial cells, its levels and shedding in senescent endothelial cells and vascular endothelial dysfunction associated with aging are still unknown.
To assess whether SDC4 expression was affected by inflammatory conditions, we evaluated its levels in young human umbilical vein endothelial cells (HUVECs) treated with TNF-α at a concentration of 50 ng/mL for 24 h and in cells undergoing replicative senescence. Plasma levels of SDC4 were evaluated in two previously recruited cohorts of (i) subjects with type 2 diabetes (T2D, n = 110) followed for a median of 16.8 years and age- and gender-matched healthy subjects (n = 100), and (ii) middle-aged subjects with mild-to-moderate dyslipidemia. Binomial logistic regression was used to assess whether SDC4 levels could be prognostic for major adverse cardiovascular events (MACE).
In the in vitro study, we showed that HUVECs, when exposed to TNF-α or undergoing replicative senescence, exhibited elevated expression levels of SDC4 and matrix metallopeptidase 9 (MMP-9), as well as increased shedding of SDC4 into the extracellular microenvironment, in comparison to actively proliferating young HUVECs. Analysis of human samples revealed that patients with T2D without complications exhibited higher SDC4 levels compared to healthy controls and those with T2D vascular complications. In particular, patients with a history of major adverse cardiovascular events (MACE) had lower SDC4 levels. The longitudinal evaluation revealed that higher SDC4 levels predict the onset of new MACE during a 16.8-year follow-up. In the second cohort, no significant association was observed between SDC4 and endothelial dysfunction, assessed by flow-mediated dilation (FMD) or nitric oxide metabolites. SDC4 levels correlated positively with C-reactive protein (CRP) in both cohorts and with PAI-1 in the cohort of patients with T2D.
Overall, we conclude that the shedding of SDC4 from endothelial cells increases under acute (TNF-α treatment) and chronic (senescence) inflammatory conditions and that increased circulating SDC4 levels are associated with systemic inflammation in pathological aging.
内皮细胞衰老正逐渐成为与年龄相关的血管功能障碍的关键机制。内皮糖萼的破坏和syndecan（SDC）胞外域的脱落与多种年龄相关疾病有关。尽管SDC4在内皮细胞中高表达，但其在衰老内皮细胞中的水平和脱落情况以及与衰老相关的血管内皮功能障碍仍不清楚。
为了评估SDC4表达是否受炎症条件影响，我们评估了其在以50 ng/mL浓度的TNF-α处理24小时的年轻人类脐静脉内皮细胞（HUVECs）以及经历复制性衰老的细胞中的水平。在两个先前招募的队列中评估了SDC4的血浆水平，队列（i）为2型糖尿病（T2D，n = 110）患者，随访中位数为16.8年，以及年龄和性别匹配的健康受试者（n = 100），队列（ii）为患有轻度至中度血脂异常的中年受试者。采用二项逻辑回归评估SDC4水平是否可预测主要不良心血管事件（MACE）。
在体外研究中，我们发现，与活跃增殖的年轻HUVECs相比，暴露于TNF-α或经历复制性衰老的HUVECs表现出SDC4和基质金属蛋白酶9（MMP-9）表达水平升高，以及SDC4向细胞外微环境中的脱落增加。对人体样本的分析显示，无并发症的T2D患者与健康对照者以及患有T2D血管并发症的患者相比，SDC4水平更高。特别是，有主要不良心血管事件（MACE）病史的患者SDC4水平较低。纵向评估显示，较高的SDC4水平可预测16.8年随访期间新MACE的发生。在第二个队列中，通过血流介导的血管舒张（FMD）或一氧化氮代谢产物评估，未观察到SDC4与内皮功能障碍之间存在显著关联。在两个队列中，SDC4水平均与C反应蛋白（CRP）呈正相关，在T2D患者队列中与纤溶酶原激活物抑制剂-1（PAI-1）呈正相关。
总体而言，我们得出结论，在急性（TNF-α处理）和慢性（衰老）炎症条件下，内皮细胞中SDC4的脱落增加，并且循环SDC4水平升高与病理性衰老中的全身炎症相关。
