Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Central Laboratory of Cardiovascular Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Interact Cardiovasc Thorac Surg. 2022 Jan 18;34(2):274-282. doi: 10.1093/icvts/ivab242.
Patients with bicuspid aortic valve (BAV) have a high risk of aortic dilation and adverse vascular events. Previous studies had reported soluble receptor for advanced glycation end products (sRAGE) to compete with receptor of advanced glycation end products (RAGE) for ligand binding and inhibit the activation of nuclear-factor kappa-B (NF-κB) pathway and matrix metalloproteinases (MMP) transcription. Thus, sRAGE serum levels may contribute to the clinical diagnosis and monitoring of ascending aorta aneurysm in patients with BAV.
To eliminate the confounding factors, 44 patients with BAV were divided into 3 subgroups according to the diameter of ascending aorta, and 20 patients with tricuspid aortic valve and normal-sized ascending aorta were selected as a control group. Protein levels and gene transcription of several variates were evaluated in the tissue and serum samples from these patients. Human aortic smooth muscle cells were treated with AGE-BSA in gradient concentrations, and changes in phenotype and protein and mRNA levels were detected.
Serum levels of sRAGE in the 3 BAV groups were obviously higher than those in the tricuspid aortic valve group, although there was negative correlation between the serum sRAGE levels and ascending aortic diameters among patients with BAV. Transcript expression levels of RAGE and NF-κBp65 mRNA were increased in the 3 BAV groups and RAGE/NF-κB pathway was activated with the progression of ascending aortic aneurysm. Abnormal activation of RAGE/NF-κB pathway was observed in AGE-BSA-treated human aortic smooth muscle cells.
Our study has shown a trend in serum levels of sRAGE among patients with BAV, and that the cellular and extracellular pathological processes are quite serious even in the normal-sized or slightly dilated aorta. Together, the findings indicated that sRAGE may be used as a biomarker to predict aneurysm expansion rates and the risk of adverse vascular events.
二叶式主动脉瓣（BAV）患者主动脉扩张和不良血管事件风险较高。既往研究报道，可溶性晚期糖基化终产物受体（sRAGE）与晚期糖基化终产物受体（RAGE）竞争配体结合，并抑制核因子-κB（NF-κB）通路和基质金属蛋白酶（MMP）转录的激活。因此，sRAGE 血清水平可能有助于 BAV 患者升主动脉瘤的临床诊断和监测。
为了消除混杂因素，根据升主动脉直径将 44 例 BAV 患者分为 3 个亚组，选择 20 例三叶式主动脉瓣和正常升主动脉大小的患者作为对照组。评估这些患者组织和血清样本中的几种变量的蛋白水平和基因转录。用人 AGE-BSA 以梯度浓度处理人主动脉平滑肌细胞，并检测表型和蛋白及 mRNA 水平的变化。
3 个 BAV 组的血清 sRAGE 水平明显高于三叶式主动脉瓣组，尽管 BAV 患者的血清 sRAGE 水平与升主动脉直径之间呈负相关。3 个 BAV 组的 RAGE 和 NF-κBp65mRNA 的转录表达水平均升高，随着升主动脉瘤的进展，RAGE/NF-κB 通路被激活。在 AGE-BSA 处理的人主动脉平滑肌细胞中观察到 RAGE/NF-κB 通路的异常激活。
我们的研究表明 BAV 患者血清 sRAGE 水平呈趋势，即使在正常大小或稍扩张的主动脉中，细胞内和细胞外的病理过程也相当严重。综上所述，这些发现表明 sRAGE 可作为预测动脉瘤扩张率和不良血管事件风险的生物标志物。
