Abstract P190: Role of mTOR Signaling in LEOPARD-Syndrome-Associated Hypertrophic Cardiomyopathy

• Published in: Circulation research 2011-12, Vol.109 (suppl_1)
• Main Authors: Krenz, Maike, Schramm, Christine, Fine, Deborah, Edwards, Michelle, Reeb, Ashley
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.109.suppl_1.AP190

Abstract only 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. In particular, how Shp2 loss-of-function (LOF) mutations cause LEOPARD Syndrome, which is characterized by congenital heart defects such as pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM), remains unclear. We employed both in vitro and in vivo models to investigate signaling mechanisms downstream of Q510E-Shp2, a particularly aggressive mutation leading to early-onset HCM. In cultured rat neonatal cardiomyocytes, Q510E-Shp2 expression significantly increased cell size. This increase was accompanied by hyperactivation of signaling through mammalian target of rapamycin (mTOR). mTOR inhibition with rapamycin reversed the pro-hypertrophic effects of Q510E-Shp2 in culture. Mice with cardiomyocyte-specific overexpression of Q510E-Shp2 starting before birth also showed up-regulation of signaling through Akt/mTOR/p70S6K and developed HCM in the early neonatal period. Q510E-Shp2 expression increased cardiomyocyte sizes and septum thickness, and caused cardiomyocyte disarray and fibrosis. Echocardiographically, hearts were hypocontractile and displayed increased wall thicknesses. Importantly, rapamycin administration rescued the Q510E-Shp2-induced phenotype in vivo. Our studies establish a role for mTOR signaling in HCM caused by the LOF mutation Q510E-Shp2. Pharmacological inhibition of mTOR was sufficient to rescue the HCM phenotype in both models. These findings have important implications not only for the development of novel therapeutic approaches for LEOPARD Syndrome patients, but also for closely related forms of congenital heart disease such as Noonan Syndrome.