Dialysis Accelerates Medial Vascular Calcification in Part by Triggering Smooth Muscle Cell Apoptosis
Dialysis Accelerates Medial Vascular Calcification in Part by Triggering Smooth Muscle Cell Apoptosis
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DOI：
10.1161/circulationaha.108.783738
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发表时间：
2008-10-21
期刊：
影响因子：
37.8
通讯作者：
Shanahan, Catherine M.
中科院分区：
文献类型：
--
作者：
Shroff, Rukshana C.;McNair, Rosamund;Shanahan, Catherine M.
背景：血管钙化与V期慢性肾脏疾病的发病率和死亡率增加有关，但其早期发病机制和体内启动机制尚不清楚。为了解决这个问题，我们量化了儿童动脉中的钙（Ca）负荷（透析前10例，透析24例），并将其与临床、生化和血管测量相关联。方法与结果：透析前和透析后血管钙负荷均显著升高，且与患者平均血清钙磷酸产物相关。然而，只有透析患者显示颈动脉内膜厚度增加，主动脉僵硬度增加，计算机断层扫描显示钙化仅出现在钙负荷最高的2例患者中。重要的是，透析前血管在组织学上是完整的，而透析血管由于细胞凋亡而表现出广泛的血管平滑肌细胞（VSMC）损失。透析血管碱性磷酸酶活性升高，Runx2和osterix表达增加，提示VSMC成骨转化。囊泡膜标志物膜联蛋白VI和囊泡成分矿化抑制剂胎蛋白a和基质玻璃蛋白的沉积在透析血管中增加，并在von Kossa阳性明显钙化之前增加。电镜显示，受损/死亡VSMCs释放的囊泡内存在羟基磷灰石纳米晶体，表明它们在钙化过程中的作用。综上所述，本研究表明，钙积累始于透析前，但透析过程中VSMC凋亡的诱导才是VSMC防御机制失效和导致明显钙化的关键事件，最终导致临床可检测到的血管损伤。因此，确定导致透析中VSMC死亡的因素对于预防血管钙化至关重要。（Circulation. 2008; 118: 1748-1757.）
Background-Vascular calcification is associated with increased morbidity and mortality in stage V chronic kidney disease, yet its early pathogenesis and initiating mechanisms in vivo remain poorly understood. To address this, we quantified the calcium (Ca) load in arteries from children (10 predialysis, 24 dialysis) and correlated it with clinical, biochemical, and vascular measures.Methods and Results-Vessel Ca load was significantly elevated in both predialysis and dialysis and was correlated with the patients' mean serum Cax phosphate product. However, only dialysis patients showed increased carotid intimamedia thickness and increased aortic stiffness, and calcification on computed tomography was present in only the 2 patients with the highest Ca loads. Importantly, predialysis vessels appeared histologically intact, whereas dialysis vessels exhibited evidence of extensive vascular smooth muscle cell (VSMC) loss owing to apoptosis. Dialysis vessels also showed increased alkaline phosphatase activity and Runx2 and osterix expression, indicative of VSMC osteogenic transformation. Deposition of the vesicle membrane marker annexin VI and vesicle component mineralization inhibitors fetuin-A and matrix Gla-protein increased in dialysis vessels and preceded von Kossa positive overt calcification. Electron microscopy showed hydroxyapatite nanocrystals within vesicles released from damaged/dead VSMCs, indicative of their role in initiating calcification.Conclusions-Taken together, this study shows that Ca accumulation begins predialysis, but it is the induction of VSMC apoptosis in dialysis that is the key event in disabling VSMC defense mechanisms and leading to overt calcification, eventually with clinically detectable vascular damage. Thus the identification of factors that lead to VSMC death in dialysis will be of prime importance in preventing vascular calcification. (Circulation. 2008; 118: 1748-1757.)