Department of Medical Pharmacology & Physiology, University of Missouri-Columbia, 65211, USA.
Am J Physiol Heart Circ Physiol. 2012 Jan 1;302(1):H231-43. doi: 10.1152/ajpheart.00665.2011. Epub 2011 Nov 4.
The identification of mutations in PTPN11 (encoding the protein tyrosine phosphatase Shp2) in families with congenital heart disease has facilitated mechanistic studies of various cardiovascular defects. However, the roles of normal and mutant Shp2 in the developing heart are still poorly understood. Furthermore, it remains unclear how Shp2 loss-of-function (LOF) mutations cause LEOPARD Syndrome (also termed Noonan Syndrome with multiple lentigines), which is characterized by congenital heart defects such as pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). In normal hearts, Shp2 controls cardiomyocyte size by regulating signaling through protein kinase B (Akt) and mammalian target of rapamycin (mTOR). We hypothesized that Shp2 LOF mutations dysregulate this pathway, resulting in HCM. For our studies, we chose the Shp2 mutation Q510E, a dominant-negative LOF mutation associated with severe early onset HCM. Newborn mice with cardiomyocyte-specific overexpression of Q510E-Shp2 starting before birth displayed increased cardiomyocyte sizes, heart-to-body weight ratios, interventricular septum thickness, and cardiomyocyte disarray. In 3-mo-old hearts, interstitial fibrosis was detected. Echocardiographically, ventricular walls were thickened and contractile function was depressed. In ventricular tissue samples, signaling through Akt/mTOR was hyperactivated, indicating that the presence of Q510E-Shp2 led to upregulation of this pathway. Importantly, rapamycin treatment started shortly after birth rescued the Q510E-Shp2-induced phenotype in vivo. If rapamycin was started at 6 wk of age, HCM was also ameliorated. We also generated a second mouse model in which cardiomyocyte-specific Q510E-Shp2 overexpression started after birth. In contrast to the first model, these mice did not develop HCM. In summary, our studies establish a role for mTOR signaling in HCM caused by Q510E-Shp2. Q510E-Shp2 overexpression in the cardiomyocyte population alone was sufficient to induce the phenotype. Furthermore, the pathomechanism was triggered pre- but not postnatally. However, postnatal rapamycin treatment could still reverse already established HCM, which may have important therapeutic implications.
PTPN11（编码蛋白酪氨酸磷酸酶 Shp2）突变的鉴定促进了各种心血管缺陷的机制研究。然而，正常和突变 Shp2 在发育心脏中的作用仍知之甚少。此外，Shp2 功能丧失（LOF）突变如何导致 LEOPARD 综合征（也称为多发性痣的 Noonan 综合征）仍不清楚，其特征是先天性心脏病，如肺动脉瓣狭窄和肥厚型心肌病（HCM）。在正常心脏中，Shp2 通过调节蛋白激酶 B（Akt）和哺乳动物雷帕霉素靶蛋白（mTOR）的信号传导来控制心肌细胞大小。我们假设 Shp2 LOF 突变会使该途径失调，导致 HCM。在我们的研究中，我们选择了 Shp2 突变 Q510E，这是一种与严重早发性 HCM 相关的显性 LOF 突变。出生前开始在心肌细胞特异性过表达 Q510E-Shp2 的新生小鼠表现出心肌细胞增大、心体比增加、室间隔厚度增加和心肌细胞排列紊乱。在 3 个月大的心脏中，检测到间质纤维化。超声心动图显示心室壁增厚，收缩功能降低。在心室组织样本中，Akt/mTOR 信号转导被过度激活，表明 Q510E-Shp2 的存在导致该途径的上调。重要的是，出生后不久开始用雷帕霉素治疗可在体内挽救 Q510E-Shp2 诱导的表型。如果在 6 周龄时开始使用雷帕霉素，HCM 也得到改善。我们还生成了第二个心肌细胞特异性 Q510E-Shp2 过表达在出生后开始的小鼠模型。与第一个模型相反，这些小鼠没有发展出 HCM。总之，我们的研究确立了 mTOR 信号在由 Q510E-Shp2 引起的 HCM 中的作用。心肌细胞群体中 Q510E-Shp2 的过表达足以诱导表型。此外，病理机制是在出生前而不是出生后触发的。然而，出生后雷帕霉素治疗仍然可以逆转已经建立的 HCM，这可能具有重要的治疗意义。
