Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease.
Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease.
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DOI：
10.1161/circulationaha.108.827972
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发表时间：
2009-04-07
期刊：
影响因子：
37.8
通讯作者：
Weissleder R
中科院分区：
文献类型：
--
作者：
Aikawa E;Aikawa M;Libby P;Figueiredo JL;Rusanescu G;Iwamoto Y;Fukuda D;Kohler RH;Shi GP;Jaffer FA;Weissleder R
临床研究表明，50%的慢性肾脏病（CRD）患者死于心血管原因，包括晚期钙化动脉和瓣膜疾病;然而，CRD加速钙化的机制仍然不清楚，没有任何治疗方法可以阻止疾病进展。我们最近在体内证实炎症触发心血管钙化。体外研究也表明，弹性蛋白降解产物可促进骨生成。在这里，我们使用转基因小鼠和分子成像来测试体内的假设，即组织蛋白酶S（catS），一种有效的弹性蛋白酶，加速钙化的动脉粥样硬化小鼠CRD诱导5/6肾切除术。将载脂蛋白缺陷（apoE−/−）/catS+/+（n = 24）和apoE−/−/catS−/−（n = 24）小鼠分配至CRD组和对照组。CRD小鼠的血清磷酸盐、肌酐和胱抑素C水平显著高于无CRD的小鼠。为了在体内可视化catS活性和成骨，我们在肾切除术后10周共同给予catS活化和钙化靶向分子成像剂。在CRD apoE−/−/catS+/+组群中，成像共记录了catS和成骨活性的增加，而CRD apoE−/−/catS−/−小鼠表现出较少的钙化。定量组织学显示，CRD apoE−/−/catS+/+中的catS相关弹性蛋白断裂和钙化程度高于CRD apoE−/−/catS−/−动脉瘤和主动脉瓣。值得注意的是，catS缺失不会引起其他弹性蛋白溶解性组织蛋白酶或基质金属蛋白酶的RNA水平代偿性增加。弹性蛋白肽和重组catS显着增加钙化平滑肌细胞在体外，一个过程中进一步放大，在富含磷酸盐的培养基。本研究提供了直接的体内证据，证明猫诱导的弹性蛋白溶解加速了CRD中的动脉和主动脉瓣钙化，为心血管钙化的病理生理学提供了新的见解。
Clinical studies have demonstrated that 50% of individuals with chronic renal disease (CRD) die of cardiovascular causes, including advanced calcific arterial and valvular disease; however, the mechanisms of accelerated calcification in CRD remain obscure, and no therapies can prevent disease progression. We recently demonstrated in vivo that inflammation triggers cardiovascular calcification. In vitro evidence also indicates that elastin degradation products may promote osteogenesis. Here, we used genetically modified mice and molecular imaging to test the hypothesis in vivo that cathepsin S (catS), a potent elastolytic proteinase, accelerates calcification in atherosclerotic mice with CRD induced by 5/6 nephrectomy. Apolipoprotein-deficient (apoE−/−)/catS+/+ (n = 24) and apoE−/−/catS−/− (n = 24) mice were assigned to CRD and control groups. CRD mice had significantly higher serum phosphate, creatinine, and cystatin C levels than those without CRD. To visualize catS activity and osteogenesis in vivo, we coadministered catS-activatable and calcification-targeted molecular imaging agents 10 weeks after nephrectomy. Imaging coregistered increased catS and osteogenic activities in the CRD apoE−/−/catS+/+ cohort, whereas CRD apoE−/−/catS−/− mice exhibited less calcification. Quantitative histology demonstrated greater catS-associated elastin fragmentation and calcification in CRD apoE−/−/catS+/+ than CRD apoE−/−/catS−/− aortas and aortic valves. Notably, catS deletion did not cause compensatory increases in RNA levels of other elastolytic cathepsins or matrix metalloproteinases. Elastin peptide and recombinant catS significantly increased calcification in smooth muscle cells in vitro, a process further amplified in phosphate-enriched culture medium. The present study provides direct in vivo evidence that catS-induced elastolysis accelerates arterial and aortic valve calcification in CRD, providing new insight into the pathophysiology of cardiovascular calcification.