ALDH2在镉促进内皮细胞凋亡及动脉粥样硬化斑块易损性中的作用及机制研究

The mechanisms of the initiation and progression of atherosclerosis are complicated and not yet well understood. More and more researches indicated that cadmium is an independent risk factor of atherosclerosis, and could affect the initiation and progression of atherosclerosis, but the precise mechanisms are still not fully understood. In our preliminary experiments, we found that cadmium with a higher concentration or a longer exposure time could decrease the proliferation of human umbilical vein endothelial cells and promote their apoptosis; and activity of ALDH2 was obviously inhibited in a dose- and time-dependent manner with an increased phosphorylation level of some Ser residues, but there were no changes of ALDH2 protein expression. Moreover, JNK inhibitor could restore the activity of ALDH2 and lead to a decrease of phosphorylation level of these Ser residues. Therefore, we put forward the hypothesis: cadmium can inhibit the activity of ALDH2 through activating JNK, subsequently phosphorylating a specific ALDH2 Ser/Thr residue, which leads to the accumulation of harmful aldehydes and inflammation, endothelial cell apoptosis and atherosclerotic plaque instability. The study aims at investigating the effect and underlying mechanisms of JNK-ALDH2 on the cadmium-induced endothelial cell apoptosis and atherosclerotic plaque vulnerability from levels of cells and animal models, in order to provide the basis for prevention and therapy of atherosclerosis.

动脉粥样硬化发生发展的机制复杂且未完全明确。越来越多的研究表明镉能够影响动脉粥样硬化的发生发展，是动脉粥样硬化的独立危险因素，但其确切机制仍不完全明了。前期研究发现较高浓度或较长时程的镉能够减弱人脐静脉内皮细胞（HUVECs）增殖、促进HUVECs凋亡，且ALDH2的活性受到明显的抑制，并具有浓度依赖性和时间依赖性，但ALDH2蛋白表达量不变，ALDH2 Ser位点磷酸化水平增加；而JNK抑制剂能使ALDH2活性恢复，Ser位点磷酸化水平降低。因此提出假说：镉激活JNK后磷酸化ALDH2某个特定的Ser/Thr位点从而抑制ALDH2的活性，导致有害醛类聚积和炎症反应，促进内皮细胞凋亡，导致动脉粥样硬化斑块不稳定。本研究拟在已有工作基础上，从细胞、动物等水平验证JNK-ALDH2在镉促进内皮细胞凋亡及动脉粥样硬化斑块易损性中的作用及机制，为动脉粥样硬化的防治提供分子生物学依据。

急性冠脉综合征（ACS）是动脉粥样硬化斑块破裂或侵蚀，继发完全或不完全性血栓形成的临床综合征。易损斑块破裂是ACS发病的重要原因，而乙醛脱氢酶2（ALDH2） 是抑制易损斑块的发生和发展的关键蛋白，镉是动脉粥样硬化的独立危险因素。但ALDH2及镉对动脉粥样硬化易损斑块的影响及其分子机制尚未完全阐明。本项目从细胞、动物等水平探讨了ALDH2对动脉粥样硬化斑块稳定性的影响及其分子机制，发现①ALDH2能够抑制炎症反应并影响动脉粥样硬化斑块稳定性；②ALDH2缺陷能够通过抑制CD36表达抑制ox-LDL诱导的泡沫细胞形成，从而影响斑块稳定性；③镉能够抑制ALDH2的活性，引起内皮细胞凋亡增加，从而影响斑块发生及稳定性；④ALDH2 Glu504Lys突变能够预测急性冠脉综合征患者预后不良。该研究能够进一步揭示ALDH2对心血管的保护机制，有助于明确ALDH2作为ACS药物靶点的临床意义，为心血管疾病的治疗策略提供新的思路和方法以及重要的科学依据。