Deficiency of cartilage oligomeric matrix protein causes dilated cardiomyopathy
Deficiency of cartilage oligomeric matrix protein causes dilated cardiomyopathy
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软骨寡聚基质蛋白缺乏导致扩张型心肌病
DOI：
10.1007/s00395-013-0374-9
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发表时间：
2013-09-01
影响因子：
9.5
通讯作者：
Kong, Wei
中科院分区：
文献类型：
--
作者：
Huang, Yaqian;Xia, Jiahong;Kong, Wei
心脏细胞外基质的改变与扩张型心肌病（DCM）及其进展为心力衰竭有关。基质细胞蛋白软骨寡聚基质蛋白（COMP）已被指示定位于心脏中。COMP−/−小鼠（雄性和雌性）在幼年（3-5个月）自发发生DCM，心脏功能受损。出生后1个月时对COMP −/−心脏的评估，尽管功能正常，但显示严重的心脏超微结构缺陷，同时伴有心肌细胞凋亡、肌丝丢失、连接蛋白-43缺乏和基质金属蛋白酶激活。与供体心脏相比，在DCM患者的心脏样品中观察到COMP表达降低。从机制上讲，COMP−/−心脏表现出整合素β1表达和信号传导减少。COMP或整合素β1的异位表达挽救了COMP缺陷诱导的心肌细胞凋亡、肌丝溶解和连接蛋白-43畸变。此外，COMP直接与整合素β1的细胞外β-尾结构域结合，阻止整合素β1泛素化/降解，并维持心脏稳态。COMP-整合素β1轴是DCM的潜在靶点。
Alterations in cardiac extracellular matrix are involved in dilated cardiomyopathy (DCM) and its progression to heart failure. The matricellular protein cartilage oligomeric matrix protein (COMP) has been indicated localized in the heart. However, the role of COMP in cardiac homeostasis and disease remains elusive.COMP−/−mice, both male and female, developed DCM spontaneously at young age (3–5 months), with impaired cardiac function. Assessment of postnatalCOMP−/−heart at 1 month, although functionally normal, revealed severe cardiac ultrastructure defect, in parallel with cardiomyocyte apoptosis, myofilament loss, connexin-43 deficiency and matrix metalloproteinase activation. Decreased COMP expression was observed in the heart sample of DCM patients compared with donor heart. Mechanistically,COMP−/−heart exhibited reduced integrin β1 expression and signaling. Ectopic expression of COMP or integrin β1 rescued COMP-deficiency-induced cardiomyocyte apoptosis, myofilament dissolution, and connexin-43 aberrance. Additionally, COMP directly bonded to the extracellular β-tail domain of integrin β1, prevented integrin β1 ubiquitination/degradation, and maintained the cardiac homeostasis. COMP-integrin β1 axis is a potential target of DCM.