高磷血症致胆固醇敏感器SCAP功能失调促进动脉粥样硬化的分子机制研究

Atherosclerotic disease is the most common complication and the main cause of death in the population suffering from chronic kidney disease(CKD). Mounting evidence showed a strong link between higher serum phosphate level and greater incidence of atherosclerotic disease. However, the mechanism remains unknown. The negative feedback regulation of LDL receptor (LDLr), which is mediated by cholesterol sensor- Sterol Regulatory Element Binding Protein (SREBP) Cleavage Activiting Protein (SCAP), is the most crucial mechanism for the maintaince of the intracellular cholesterol homeostasis. Our previous study indicated that hyperphosphatemia promoted lipid accumulation in primary human vascular smooth muscle cells (hVSMCs), and increased the expression of SCAP in a dose dependent manner, which might lead to the aberrant translocation of SCAP from ER to Golgi. We supposed that hyperphosphatemia may promote intracellular lipid accumulation and atheroma progression by inducing the dysfunction of SCAP. . This study will target the mechanisms by which hyperphosphatemia promotes atherosclerosis. The methods of cell culture, animal experiments, human vascular ring culture and clinical case-control study will be used to examine our hypothesis— hyperphosphatemia disrupts SCAP mediated cholesterol homestasis feedback regulation, by which it upregulates the expression of LDLr and HMGCoAR, facilitates excessive exotic LDL uptake and intracellular cholesterol denove synthesis, results in excessive lipid accumulation in the cells and the progression of atheroma. The effectiveness of serum phosphorus control to the prevention and treatment of atherosclerotic disease will be evaluated, which is expected to give indications for the prescription of phosphate binding agents during clinical practice.

动脉粥样硬化性疾病是慢性肾脏病患者最常见的并发症和首要死亡原因。大量研究发现血磷增高能够显著增加慢性肾脏病患者动脉粥样硬化性疾病的发生率，但机制并不清楚。胆固醇敏感器SCAP介导的对LDL受体活性的负反馈调节是维持细胞内胆固醇稳态的重要生理机制。我们前期研究发现：高磷状态能够促进原代人VSMCs内脂质聚集，并呈剂量依赖性地增加胆固醇敏感器SCAP的表达，促进其向高尔基体异常转位。因此，我们推测，高磷血症可能通过诱导胆固醇敏感器SCAP功能失调促进细胞内脂质积聚及动脉粥样硬化的发生。.本项目拟通过细胞试验、动物实验、人动脉血管环培养及临床病例对照研究，探索高磷血症促进动脉粥样硬化性疾病的分子机制，并从分子、细胞和整体水平系统评价降血磷治疗对防治高磷血症所致动脉粥样硬化性疾病的效果。研究结果可能为高磷血症所致动脉粥样硬化性疾病的防治提供潜在的新靶点，并为降血磷药物的临床应用提供新的理论依据。

背景：慢性肾脏病（CKD）患者的动脉粥样硬化（AS）被称为“加速性动脉粥样硬化”。动脉粥样硬化性心血管疾病（ASCVD）是CKD患者最主要的死亡原因。高磷血症在AS的发生与发展中扮演了重要角色，然而其致AS的分子机制目前仍不清楚。主要研究内容：本课题通过一系列体内外实验，深入探讨了高磷血症通过干扰细胞内源性胆固醇合成促进AS的分子机制。重要结果及数据：（1）通过横断面研究证实：高磷血症在中国CKD人群中具有类似于欧美人群的促ASCVD作用，血磷水平越高，ASCVD风险越高；（2）建立高磷血症小鼠动脉粥样硬化模型，证实血磷水平与AS斑块面积存在正相关关系；（3）深入探索高磷血症促ASCVD分子机制发现：增高的血磷通过VSMC表面磷转运体进入细胞内，异常上调alpha-甘露糖苷酶活性，促进SCAP异常糖基化修饰，糖基化的SCAP异常循环转运激活SREBP2，产生过多SREBP2-N，后者转位入核并作为转录因子增强胆固醇内源性合成限速酶HMGCR的基因转录，增高HMGCR水平，最终导致细胞内源性胆固醇合成增多；在磷跨膜转运、SCAP异常糖基化等关键步骤给予药物干预可能阻断高磷血症的促ASCVD作用。科学意义：本课题的研究结果深入揭示了高磷血症促进ASCVD的分子机制，深化了人们对高磷血症促ASCVD作用的认识；为高磷血症所致的ASCVD的预防和治疗提供潜在的新靶点；为临床使用磷结合剂等降血磷药物提供新的理论依据。