Xu Junwang, Ismat Fraz A, Wang Tao, Lu Min Min, Antonucci Nicole, Epstein Jonathan A
Department of Cell and Developmental Biology and the Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Circ Res. 2009 Jul 31;105(3):304-11. doi: 10.1161/CIRCRESAHA.109.201509. Epub 2009 Jul 2.
Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with a broad array of clinical manifestations, including benign and malignant tumors, and characteristic cutaneous findings. NF1 patients also have an increased incidence of cardiovascular diseases, including obstructive vascular disorders and hypertension. The disease gene, NF1, encodes neurofibromin, a ubiquitously expressed protein that acts, in part, as a Ras-GAP (GTP-ase activating protein), downregulating the activity of activated Ras protooncogenes. In animal models, endothelial and smooth muscle expression of the disease gene is critical for normal heart development and the prevention of vascular disease, respectively.
To determine the role of NF1 in the postnatal and adult heart.
We generated mice with homozygous loss of the murine homolog Nf1 in myocardium (Nf1mKO) and evaluated their hearts for biochemical, structural, and functional changes. Nf1mKO mice have normal embryonic cardiovascular development but have marked cardiac hypertrophy, progressive cardiomyopathy, and fibrosis in the adult. Hyperactivation of Ras and downstream pathways are seen in the heart with the loss of Nf1, along with activation of a fetal gene program.
This report describes a critical role of Nf1 in the regulation of cardiac growth and function. Activation of pathways known to be involved in cardiac hypertrophy and dysfunction are seen with the loss of myocardial neurofibromin.
1型神经纤维瘤病（NF1）是一种常见的常染色体显性疾病，具有广泛的临床表现，包括良性和恶性肿瘤以及特征性皮肤表现。NF1患者患心血管疾病的发生率也增加，包括阻塞性血管疾病和高血压。疾病基因NF1编码神经纤维瘤蛋白，这是一种普遍表达的蛋白质，部分作为Ras-GAP（GTP酶激活蛋白）发挥作用，下调活化的Ras原癌基因的活性。在动物模型中，疾病基因在内皮和平滑肌中的表达分别对正常心脏发育和预防血管疾病至关重要。
确定NF1在出生后和成年心脏中的作用。
我们构建了心肌中鼠同源基因Nf1纯合缺失的小鼠（Nf1mKO），并评估其心脏的生化、结构和功能变化。Nf1mKO小鼠胚胎期心血管发育正常，但成年后出现明显的心脏肥大、进行性心肌病和纤维化。随着Nf1缺失，心脏中Ras及其下游通路过度激活，同时伴有胎儿基因程序的激活。
本报告描述了Nf1在调节心脏生长和功能中的关键作用。随着心肌神经纤维瘤蛋白的缺失，可观察到已知参与心脏肥大和功能障碍的通路被激活。
