Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Peking University, Beijing, 100191, People's Republic of China.
Basic Res Cardiol. 2013 Sep;108(5):374. doi: 10.1007/s00395-013-0374-9. Epub 2013 Aug 6.
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 postnatal COMP (-/-) 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.
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。细胞基质蛋白软骨寡聚基质蛋白（COMP）已被证明定位于心脏。然而，COMP 在心脏稳态和疾病中的作用仍不清楚。COMP（-/-）雄性和雌性小鼠在年轻时（3-5 个月）自发发生 DCM，伴有心脏功能受损。尽管功能正常，但对 1 个月大的 COMP（-/-）心脏进行评估显示出严重的心脏超微结构缺陷，同时伴有心肌细胞凋亡、肌丝丧失、连接蛋白-43 缺乏和基质金属蛋白酶激活。与供体心脏相比，DCM 患者的心脏样本中 COMP 的表达降低。从机制上讲，COMP（-/-）心脏表现出整合素 β1 表达和信号的减少。COMP 或整合素 β1 的异位表达挽救了 COMP 缺乏诱导的心肌细胞凋亡、肌丝溶解和连接蛋白-43 异常。此外，COMP 直接与整合素 β1 的细胞外β-尾部结构域结合，防止整合素 β1 的泛素化/降解，并维持心脏稳态。COMP-整合素 β1 轴是 DCM 的一个潜在靶点。
