精氨酸酶活性升高是高磷致血管内皮细胞损伤的重要机制

Hyperphosphatemia is related with highmorbidityand mortality of cardiovascular disease(CVD) in patients with chronickidneydisease(CKD)by inducing apoptosis of vascular endothelial cells. Our previous study found that: 1）Hyperphosphatemia could induce apoptosis of human umbilical vein endothelialcells (HUVEC). 2）Metabonomicsfindings are highly suggested that elevation of the activity of Arginase(Arg), which is a key regulatory enzyme in omithine cycle, is involved in the apoptosis process induced by high phosphorus.3)Arglevel in high serum phosphorus group is higher than that in normalserum phosphorusgroup in patients with CKD stage 3. 4) In vitro, theactivity of Arg in HUVEC was enhanced by high phosphorus. It was reported that oxysterol could promote pi-induced vascular calcificationthrough RhoA/ROCKpathway; signal RhoA/ROCK and p38 MAPK are important in Arg-related CVD. we propose that: high phosphorusmay enhance theactivity of Arg in HUVEC by activatingRhoA/ROCK/p38 MAPK pathway,and then decrease theproduction of NO, and finally inducingapoptosis of endothelial cells.For furtherverification,this study intends to: analyze the key protein expression in RhoA/ROCK/p38 MAPK pathway in high phosphorus incubated HUVEC, and then verify themolecularmechanisminrats with high phosphorus diet. This study may provide potential therapeutic target for newdrugsin the intervention of hyperphosphatemiarelatedCVD in CKD patients.

高血磷是慢性肾脏病（CKD）患者发生心血管疾病（CVD）的独立危险因素。体外研究发现：高血磷可诱导血管内皮细胞损伤而参与CVD的发生发展，但机制不明。我们前期研究发现：1）高磷可诱导人脐静脉内皮细胞（HUVEC）凋亡；2）代谢组学研究示，鸟氨酸循环调节酶——精氨酸酶（Arg）活性升高与高磷诱导HUVEC凋亡相关；3）CKD3期合并高血磷患者的血Arg水平较正常血磷者高；4）高磷可诱导HUVEC的 Arg活性升高。有证据表明胆固醇可通过RhoA/ROCK增加高磷诱导的血管钙化，而Arg致血管损伤可能与p38 MAPK信号通路相关。我们认为：高磷可通过激活RhoA/ROCK/p38 MAPK这一信号通路增强Arg活性，进而诱导内皮细胞凋亡。本研究拟进一步通过体内体外实验明确血磷与Arg关系，阐明高磷诱导内皮细胞损伤的机制。预期结果将为后续探索药物治疗高磷相关CVD提供实验依据。