外源性apoA-I干预糖化apoA-I致糖尿病时动脉粥样硬化发生的研究

我们发现，糖尿病时apoA-I发生非酶促糖化，与CAD严重度相关。糖化apoA-I重组蛋白（G-apoA-I）诱导炎症、脂质逆转运异常和动脉粥样硬化（AS）。机制研究中，G-apoA-I显著上调内皮和巨噬细胞内contactin 4-PTPRG和核受体NR0B1，此二者都促进炎症、脂质转运异常和小鼠AS，表明它们是介导G-apoA-I致AS的关键环节。而apoA-I则下调此二者，抑制炎症和AS。外源性apoA-I抑制G-apoA-I诱导的炎症和AS。但仍不明确apoA-I能否干预糖尿病时体内糖化apoA-I诱导的AS和相关病理。后续将用促体内糖化的GLO1-/-小鼠等探讨外源性apoA-I能否干预：①体内apoA-I高表达且显著糖化的糖尿病小鼠AS发生；②体内糖化apoA-I和G-apoA-I诱导的脂质逆转运异常；③体内糖化apoA-I和G-apoA-I导致AS的关键致病环节，并阐明机制。

Our study has shown that apolipoprotein A-I (apoA-I) undergoes non-enzymatic glycation in diabetic patients and that glycation of apoA-I is associated with the severity of coronary artery disease in diabetes. Glycated apoA-I recombinant protein (G-apoA-I) induced vascular inflammation, endothelial dysfunction, reverse cholesterol transport impairment and atherosclerosis in apoE-/- mice. To decipher the mechanisms of G-apoA-I-inducing pathology, we stimulated aortic endothelial cells and macrophages with G-apoA-I, apoA-I or PBS control. After RNAseq analysis and the investigation of in vitro/in vivo experiments, G-apoA-I was shown to upregulate the pathways of contactin 4-PTPRG and nuclear receptor NR0B1. Further experiments displayed that activation of these pathways and nuclear receptor promoted vascular inflammation, endothelial dysfunction, reverse cholesterol transport impairment and atherogenesis, indicating that these pathways being crucial mediators of glycated apoA-I-induced pathogenesis. However, apoA-I inhibited these pathways and attenuated atherogenesis in apoE-/- mice. It has been reported that apoA-I Milano (R173C) recombinant protein and apoA-I peptide mimics inhibit plaque progression in non-diabetic patients with acute coronary syndrome. In our experiments, exogenous apoA-I recombinant protein inhibited G-apoA-I-induced atherogenesis in apoE-/- mice. But, it remains unclear whether exogenous apoA-I works effectively to prevent atherogenesis in diabetes where abnormal apoA-I function exhibits due to glycation. Our future researches will figure out: ① whether exogenous apoA-I is able to intervene atherogenesis in diabetic mice with severe endogenous apoA-I glycation; ②whether exogenous apoA-I antagonizes endogenously glycated apoA-I- or G-apoA-I-induced reverse cholesterol transport impairment; ③ whether exogenous apoA-I abrogates crucial key mediators of endogenously glycated apoA-I- or G-apoA-I-induced pathogenesis, such as contactin 4-PTPRG and nuclear receptor NR0B1.