The role of CAP2 in sex-related myocardial function

总结 心脏性猝死每年导致18万至45万美国人死亡。在无冠状动脉的患者中 疾病，猝死的风险最高的是那些有心肌病和心室内 传导延迟此外，男性经历猝死的频率几乎高出三倍 而这种性别偏见的原因尚不清楚。确定潜在的机制 心肌病和传导障碍可以改善对有猝死风险的患者的筛查， 或从心脏骤停中复苏的人的结果。到目前为止，大多数已知的突变， 心肌病存在于肌节细胞骨架蛋白中，而大多数家族性心脏传导 疾病（CCD）是由离子通道或通道相互作用蛋白的突变引起的。然而，在这方面， 细胞骨架蛋白的突变也可引起CCD，但将细胞骨架与 CCD还没有得到很好的理解。6号染色体（6p22）上有一个或多个基因与 细胞骨架蛋白CAP2（Cyclase Associated Protein 2）附近的心脏性猝死。帽 广泛保守的细胞骨架蛋白。我们首先在酵母中鉴定出CAP是一种腺苷酸环化酶结合蛋白， 蛋白此外，所有CAP同源物都是肌动蛋白单体结合蛋白，其调节平衡， 在肌动蛋白丝和肌动蛋白单体之间。哺乳动物有两种CAP亚型，CAP 1和CAP 2。到 为了确定CAP2在体内的功能，我们产生了CAP2敲除（CAP2-KO）小鼠，两者都是完整的 身体和条件。我们的初步数据显示，全身CAP2-KO小鼠出生时是活的，但 许多人在出生后不久突然死亡，只有约30%的雄性CAP2-KO存活超过12周。 CAP2-KO小鼠发展出具有轻度扩张型心肌病（DCM）的CCD。传导表型为 在心肌细胞特异性CAP2-KO小鼠中渗透性更强，所有小鼠均死于完全性心脏传导阻滞 25周。此外，全基因组分析显示，一些转录网络， 包括血清反应因子（SRF）网络在内的所有免疫调节因子在CAP2-KO小鼠的心脏中上调。 基于这些发现，我们假设CAP2通过调节 SRF信号和纤维化反应在性别特异性的方式。这些研究与 了解细胞骨架和性别特异性在心脏传导和突发性心脏病中的作用， 心源性死亡为了检验这一假设，我们提出了以下具体目标： 为了验证这一假设，我们建议：（1）确定CAP2在心脏中的具体作用， 传导系统（2）确定CAP2在血清应答因子（SRF）信号传导中的作用，和（3） 确定分泌型卷曲相关蛋白2在CAP2性别特异性心脏性猝死中的作用 小鼠

Summary Sudden cardiac death kills 180,000 to 450,000 Americans annually. In patients without coronary artery disease, the highest risk of sudden death is in those with cardiomyopathy and intraventricular conduction delay. Furthermore, males experience sudden death almost three times more frequently than females and the reasons for this sex bias are unclear. Identifying the mechanisms underlying cardiomyopathy and conduction disorders may improve screening for patients at risk for sudden death, or outcomes of those revived from cardiac arrest. To date, most known mutations that cause cardiomyopathy are in sarcomere cytoskeletal proteins whereas most familial cardiac conduction diseases (CCD) are caused by mutations in ion channels or channel interacting proteins. However, mutations in cytoskeletal proteins can also cause CCD but the mechanisms linking the cytoskeleton to CCD are not well understood. There is a gene or genes on chromosome 6 (6p22) associated with sudden cardiac death near the cytoskeletal protein CAP2 (Cyclase Associated Protein 2). CAPs are widely conserved cytoskeleton proteins. We first identified CAP in yeast as an adenylyl cyclase binding protein. Additionally, all CAP homologs are actin monomer binding proteins that regulate the balance between actin filaments and actin monomers. Mammals have two CAP isoforms, CAP1 and CAP2. To determine the function of CAP2 in vivo we generated CAP2 knockout (CAP2-KO) mice, both whole body and conditional. Our preliminary data show that whole body CAP2-KO mice are born alive, but many die suddenly shortly after birth, with only ~30% of male CAP2-KO surviving beyond 12 weeks. CAP2-KO mice develop CCD with mild dilated cardiomyopathy (DCM). The conduction phenotypes are more penetrant in cardiomyocyte-specific CAP2-KO mice, with all mice dying of complete heart block by 25 weeks. Furthermore, genome-wide analysis revealed that several transcriptional networks, including the serum response factor (SRF) network, were upregulated in the hearts of CAP2-KO mice. Based on these findings we hypothesize CAP2 maintains cardiac conduction by modulating SRF signals and fibrotic responses in a sex-specific manner. These studies are relevant to understanding the role of the cytoskeleton and gender specificity in cardiac conduction and sudden cardiac death. To test this hypothesis, we propose the following specific aims: To test this hypothesis, we propose to (1) Determine the specific role of CAP2 in the cardiac conduction system (2) Determine the role of CAP2 in serum response factor (SRF) signaling, and (3) Determine the role of Secreted Frizzled-related protein 2 in sex-specific sudden cardiac death in CAP2 mice.