Evidence for a Functional Role of the Molecular Chaperone Clusterin in Amyloidotic Cardiomyopathy
Evidence for a Functional Role of the Molecular Chaperone Clusterin in Amyloidotic Cardiomyopathy
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DOI：
10.1016/j.ajpath.2010.11.015
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发表时间：
2011-01-01
影响因子：
6
通讯作者：
Connor, Lawreen H.
中科院分区：
文献类型：
--
作者：
Greene, Michael J.;Sam, Flora;Connor, Lawreen H.
分子伴侣，包括胞外蛋白簇蛋白(CLU)，在维持蛋白质稳定方面发挥着重要作用；它们具有独特的结合和稳定非天然蛋白质构象、防止聚集和保持蛋白质处于可溶折叠能力状态的能力。在这项研究中，我们研究了淀粉样蛋白浸润性心肌组织中CLU的存在，并测量了患有和不患有淀粉样心肌病(CMP)的患者的血清CLU水平。用免疫组织化学技术检测了9例淀粉样变性CMP患者心脏组织中含有转甲状腺素(TIR)或Ig轻链的淀粉样沉淀物是否存在CLU。CLU染色与家族性TTR、老年全身性和Ig轻链淀粉样变性患者的心肌细胞外淀粉样蛋白沉积相吻合。免疫金电子显微镜证实CLU与心脏淀粉样蛋白沉积有关。测定了家族性TTR型、老年型全身型和Ig轻链淀粉样变性患者的血清CLU浓度，并与年龄匹配的健康对照组和与淀粉样变性疾病无关的CMP型患者进行了比较。基于心脏受累的疾病队列亚组分析表明，血清CLU浓度降低与淀粉样变性MP有关。综上所述，这些结果提示CLU可能在TTR和Ig轻链淀粉样变性和淀粉样变性CMP中起致病作用。(Am J Pathol 2011,178：61-68；DOI.10.1016/j.ajpath.2010.11.015)
Molecular chaperones, including the extracellular protein clusterin (CLU), play a significant role in maintaining proteostasis; they have a unique capacity to bind and stabilize non-native protein conformations, prevent aggregation, and keep proteins in a soluble folding-competent state. In this study, we investigated amyloid-infiltrated cardiac tissue for the presence of CLU and measured serum levels of CLU in patients with and without amyloidotic cardiomyopathy (CMP). Cardiac tissues containing amyloid deposits composed of either transthyretin (TIR) or Ig light chain from nine patients with amyloidotic CMP were examined for the presence of CLU using immunohistochemical techniques. CLU staining coincided with the extracellular myocardial amyloid deposits in tissues from patients with familial TTR, senile systemic, and Ig light chain amyloidosis. The association of CLU with cardiac amyloid deposits was confirmed by immunogold electron microscopy. Serum concentrations of CLU were measured in familial TTR, senile systemic, and Ig light chain amyloidosis patient groups and compared with both age-matched healthy controls and with patients with CMP unrelated to amyloid disease. Subset analysis of disease cohorts, based on cardiac involvement, indicated that decreased serum CLU concentrations were associated with amyloidotic CMP. Taken together, these results suggest that CLU may play a pathogenetic role in TTR and Ig light chain amyloidoses and amyloidotic CMP. (Am J Pathol 2011, 178:61-68; DOI. 10.1016/j.ajpath.2010.11.015)