【作者】 何芳；

【导师】 甘华；

【作者基本信息】 重庆医科大学 ， 内科学， 2018， 硕士

【摘要】 血管钙化在老年、肥胖、糖尿病以及慢性肾脏病(Chronic Kidney Disease,CKD)等疾病中很常见,是CKD的一个常见且严重的并发症,它是心血管疾病(Cardiovascular Disease,CVD)的一个非常重要的独立危险因子。研究已证实,在CKD中,高磷为诱导血管钙化发生和发展的关键因素,但是其中的具体机制还不清楚。本研究主要探讨在VSMCs中高磷与骨形态蛋白9(BMP9)之间的关系,BMP9对VSMCs钙化的影响和环氧合酶2(COX-2)对BMP9诱导的VSMCs钙化的影响,以及这一过程潜在的机制。我们研究发现,在VSMCs中高磷能明显上调BMP9的表达,BMP9过表达能明显降低α-SMA的表达,而增加Runx-2、Dlx-5和ALP的表达。同时,BMP9能增加OPN、OCN的表达水平,促进VSMCs矿化以及诱导大鼠胸主动脉钙化。高磷和过表达BMP9都能增加COX-2的表达水平;过表达COX-2能够增强BMP9对α-SMA(alpha-smooth muscle cell actin)的抑制作用以及 BMP9 诱导的OPN、OCN水平的升高。然而抑制COX-2后能减轻BMP9诱导的VSMCs和大鼠胸主动脉钙化。在机制方面我们发现,高磷或BMP9能增加VSMCs β-catein和p-GSK3β的表达;COX-2抑制剂能减少BMP9诱导的β-catein表达。我们的研究结果表明,BMP9能够诱导血管钙化的发生且CXO-2可能通过Wnt/β-catenin信号对BMP9诱导的血管钙化进行调节。更多还原

【Abstract】 Vascular calcification is common in aging,obesity,diabetes and chronic kidney disease(CKD).It is a common complication of CKD and a seriously dependent risk factor of Cardiovascular Disease(CVD).It has been investigated that high phosphate is a crucial factor of vascular calcificationIn in CKD,but the detail mechanism underlying this process remains unclear.the present study,we Determined the relationship between high phosphate and bone morphogenetic protein 9(BMP9)in VSMCs,the effect of BMP9 on calcification in VSMCs and the effect of COX-2 on BMP9 induced calcification in VSMCs,as well as the possible mechanism underlying this biological process.We found that high phosphate obviously up-regulates the expression of BMP9 in VSMCs.Over-expression of BMP9 decreases the level of alpha-smooth muscle cell actin(a-SMA)apparently,but increases the level of Runx-2,Dlx-5,and ALP in VSMCs.Meanwhile,BMP9 Increases the level of OPN and OCN,promotes mineralization in VSMCs and induces calcification in thoracic aorta.High phosphate and over-expression of BMP9 increases the level of COX-2.Over-expression of COX-2 enhances the inhibitory effect of BMP9 onα-SAM and increases the level of OPN and OCN induced by BMP9.However,inhibition of COX-2 decreases the BMP9-induced calcification in VSMCs and thoracic aorta.For mechanism,we found that high phosphate or BMP9 increases the level of β-catenin and p-GSK3β in VSMCs,but no substantial effect on GSK3β.However,COX-2 inhibitor decreases the expression of β-caten ininduced by BMP9.Our findings indicated that BMP9 is involved in the phosphate-induced calcification in VSMCs and COX-2 partly mediates the BMP9-induced calcification in VSMCs through activating Wnt/β-catenin pathway.更多还原