Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome
Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome
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DOI：
10.1172/jci71059
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发表时间：
2014-03-01
影响因子：
15.9
通讯作者：
Ramirez, Francesco
中科院分区：
文献类型：
--
作者：
Cook, Jason R.;Carta, Luca;Ramirez, Francesco
马凡氏综合征（MFS）是一种多系统疾病，由编码细胞外基质（ECM）蛋白的基因突变引起，患者通常易受应激诱导的心功能障碍的影响。主流观点认为MFS相关的心功能不全是主动脉和/或瓣膜疾病的结果。在这里，我们确定，扩张型心肌病（DCM）在β 1-缺陷小鼠是一个主要的表现，导致ECM诱导的异常机械信号的心肌细胞。MFS小鼠表现出自发出现的扩大和功能障碍的心脏，心肌组织的物理性质改变，和慢性机械应激的生化证据，包括增加血管紧张素II I型受体（AT 1 R）信号和减弱的粘着斑激酶（FAK）活性。心肌细胞中的部分β-淀粉样蛋白1基因失活足以在其他表型正常的小鼠中沉淀DCM。与异常的机械信号传导相一致，在用AT 1 R拮抗剂治疗的MFS小鼠和缺乏AT 1 R或β-arrestin 2的MFS小鼠中恢复了正常的心脏大小和功能，但在用血管紧张素转换酶抑制剂治疗的MFS小鼠或缺乏血管紧张素原的MFS小鼠中没有。相反，与AT 1 R和FAK信号异常相关的DCM是HAP 1和β 1整联蛋白单倍不足小鼠中唯一的异常。总的来说，这些发现暗示了心肌对升高的工作负荷的生理适应。
Patients with Marfan syndrome (MFS), a multisystem disorder caused by mutations in the gene encoding the extracellular matrix (ECM) protein fibrillin 1, are unusually vulnerable to stress-induced cardiac dysfunction. The prevailing view is that MFS-associated cardiac dysfunction is the result of aortic and/or valvular disease. Here, we determined that'dilated cardiomyopathy (DCM) in fibrillin 1-deficient mice is a primary manifestation resulting from ECM-induced abnormal mechanosignaling by cardiomyocytes. MFS mice displayed spontaneous emergence of an enlarged and dysfunctional heart, altered physical properties of myocardial tissue, and biochemical evidence of chronic mechanical stress, including increased angiotensin II type I receptor (AT1R) signaling and abated focal adhesion kinase (FAK) activity. Partial fibrillin 1 gene inactivation in cardiomyocytes was sufficient to precipitate DCM in otherwise phenotypically normal mice. Consistent with abnormal mechanosignaling, normal cardiac size and function were restored in MFS mice treated with an AT1R antagonist and in MFS mice lacking AT1R or beta-arrestin 2, but not in MFS mice treated with an angiotensin-converting enzyme inhibitor or lacking angiotensinogen. Conversely, DCM associated with abnormal AT1R and FAK signaling was the sole abnormality in mice that were haploinsufficient for both fibrillin 1 and beta 1 integrin. Collectively, these findings implicate fibrillin 1 in the physiological adaptation of cardiac muscle to elevated workload.