Zheng Hui, Qiu Zhihuang, Chai Tianci, He Jian, Zhang Yuling, Wang Chaoyun, Ye Jianqiang, Wu Xiaohui, Li Yumei, Zhang Li, Chen Liangwan
Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
Key Laboratory of Cardio-Thoracic Surgery (Fujian Medical University), Fuzhou, China.
Front Cardiovasc Med. 2022 Feb 3;8:732122. doi: 10.3389/fcvm.2021.732122. eCollection 2021.
Insulin resistance (IR) plays a key role in the development of type 2 diabetes mellitus (T2DM) and is one of its most important characteristics. Previous studies have shown that IR and T2DM were independent risk factors for a variety of cardiovascular and cerebrovascular diseases. However, there are few studies on the relationship between IR and aortic dissection (AD). The goal of this research was to find evidence that IR promotes the occurrence of AD.
Through the statistical analysis, we determined the proportion of glycosylated hemoglobin (HbA1c) abnormalities (HbA1c > 5.7) in people with acute thoracic aortic dissection (ATAD) and compared the difference of messenger RNA (mRNA) and protein expression of GluT1 in the thoracic aorta of normal people and those with ATAD to find evidence that IR is a causative factor in AD. The mouse model of IR and AD and the IR model of human aortic vascular smooth muscle cells (HA-VSMC) were established. Real time-PCR (RT-PCR) and Western blotting were used to study the mRNA and protein expression. Hematoxylin and eosin (H&E), Masson, and elastic fiber staining, and immunofluorescence were used to study the morphological structure.
The proportion of HbA1c abnormalities in patients with ATAD was 59.37%, and the mRNA and protein expression of GluT1 were significantly lower than that in normal people. Fasting glucose concentration (FGC), serum insulin concentration (SIC), and the homeostasis model assessment of insulin resistance (HOMA-IR) of mice was obviously increased in the high-fat diet group and the protein expressions of Glut1 and GluT4 were reduced, indicating that the mouse IR model was successfully established. The incidence of AD was different between the two groups (IR: 13/14, Ctrl: 6/14), and the protein expression of MMP2, MMP9, and OPN were upregulated and SM22 and α-SMA were downregulated in mice. The expressions of mRNA and protein of GluT1 and SM22 in HA-VSMCs with IR were reduced and OPN was increased.
Combined results of clinical findings, mouse models, and cell experiments show that IR induced the phenotypic switching of vascular smooth muscle cells (VSMCs) from contractile to synthetic, which contributes to the occurrence of AD. It provides a basis for further research on the specific mechanism of how IR results in AD and a new approach for the prevention and treatment of AD.
胰岛素抵抗（IR）在2型糖尿病（T2DM）的发生发展中起关键作用，是其最重要的特征之一。既往研究表明，IR和T2DM是多种心脑血管疾病的独立危险因素。然而，关于IR与主动脉夹层（AD）之间关系的研究较少。本研究的目的是寻找IR促进AD发生的证据。
通过统计分析，我们确定了急性胸主动脉夹层（ATAD）患者糖化血红蛋白（HbA1c）异常（HbA1c>5.7）的比例，并比较了正常人和ATAD患者胸主动脉中葡萄糖转运蛋白1（GluT1）的信使核糖核酸（mRNA）和蛋白表达差异，以寻找IR是AD致病因素的证据。建立了IR和AD的小鼠模型以及人主动脉血管平滑肌细胞（HA-VSMC）的IR模型。采用实时荧光定量聚合酶链反应（RT-PCR）和蛋白质印迹法研究mRNA和蛋白表达。采用苏木精-伊红（H&E）染色、Masson染色、弹性纤维染色及免疫荧光法研究形态结构。
ATAD患者中HbA1c异常的比例为59.37%，GluT1的mRNA和蛋白表达均显著低于正常人。高脂饮食组小鼠的空腹血糖浓度（FGC）、血清胰岛素浓度（SIC）及胰岛素抵抗稳态模型评估（HOMA-IR）明显升高，葡萄糖转运蛋白1（Glut1）和葡萄糖转运蛋白4（GluT4）的蛋白表达降低，表明成功建立了小鼠IR模型。两组AD的发生率不同（IR组：13/14，对照组：6/14），小鼠中基质金属蛋白酶2（MMP2）、基质金属蛋白酶9（MMP9）和骨桥蛋白（OPN）的蛋白表达上调，平滑肌肌动蛋白2（SM22）和α-平滑肌肌动蛋白（α-SMA）的表达下调。IR的HA-VSMC中GluT1和SM22的mRNA和蛋白表达降低，OPN表达增加。
临床研究结果、小鼠模型和细胞实验的综合结果表明，IR诱导血管平滑肌细胞（VSMC）从收缩型向合成型表型转换，这有助于AD的发生。为进一步研究IR导致AD的具体机制提供了依据，也为AD的防治提供了新的途径。
