National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
Exp Cell Res. 2011 May 1;317(8):1226-37. doi: 10.1016/j.yexcr.2011.01.020. Epub 2011 Jan 26.
The muscle-specific protein NRAP is concentrated at cardiac intercalated disks, plays a role in myofibril assembly, and is upregulated early in mouse models of dilated cardiomyopathy. Using a tet-off system, we developed novel transgenic lines exhibiting cardiac-specific NRAP overexpression ~2.5 times greater than normal. At 40-50 weeks, NRAP overexpression resulted in dilation and decreased ejection fraction in the right ventricle, with little effect on the left ventricle. Expression of transcripts encoding brain natriuretic peptide and skeletal α-actin was increased by cardiac-specific NRAP overexpression, indicative of a cardiomyopathic response. NRAP overexpression did not alter the levels or organization of N-cadherin and connexin-43. The results show that chronic NRAP overexpression in the mouse leads to right ventricular cardiomyopathy by 10 months, but that the early NRAP upregulation previously observed in some mouse models of dilated cardiomyopathy is unlikely to account for the remodeling of intercalated disks and left ventricular dysfunction observed in those cases.
肌特异性蛋白 NRAP 集中在心脏闰盘处，在肌原纤维组装中发挥作用，并在扩张型心肌病的小鼠模型中早期上调。我们使用 tet-off 系统开发了新型转基因系，其心脏特异性 NRAP 表达水平比正常水平高约 2.5 倍。在 40-50 周时，NRAP 过表达导致右心室扩张和射血分数降低，对左心室影响很小。心脏特异性 NRAP 过表达导致脑钠肽和骨骼α-肌动蛋白编码转录本的表达增加，表明存在心肌病反应。NRAP 过表达并未改变 N-钙黏蛋白和连接蛋白 43 的水平或组织。结果表明，在小鼠中慢性 NRAP 过表达导致 10 个月时右心室心肌病，但以前在一些扩张型心肌病的小鼠模型中观察到的早期 NRAP 上调不太可能解释在这些情况下观察到的闰盘重塑和左心室功能障碍。
