Abstract 300: The Role of Rheb-mTORC1 Pathway in Cardiac Developmental Growth and Pathological Hypertrophy
Mammalian target of rapamycin (mTOR) is an evolutionary conserved Ser/Thr kinase and plays a key role in cellular growth. Multiprotein complexes called mTOR complex 1 (mTORC1) signaling is essential in cardiac hypertrophy. Many signaling pathways which can regulate mTORC1 activity have been previously reported, however, the regulation of mTORC1 is not fully elucidated. A small GTPase, Rheb (Ras homologue enriched in brain)-GTP activates mTORC1. In this study, to examine the contribution of Rheb in mTORC1 signaling in vivo hearts, we generated floxed Rheb mice to obtain cardiac-specific Rheb-deficient mice. First, to examine the role of Rheb-mTORC1 pathway in developmental cardiac hypertrophy, we generated Rheb-/- mice by crossing Rhebflox/flox mice with alpha MHC-Cre transgenic mice. Rheb-/- were born in Mendelian ratio. Echocardiographic analysis revealed that chamber dimension and contractile function of Rheb-/- were similar compared to those of control mice (Rheb+/+) 5 days after birth. However, all of them died between 8 and 10 days after birth due to cardiac dysfunction and heart failure. Rheb-/- exhibited cardiac dilatation and reduced contractility 8 days after birth. The heart weight to body weight ratio and the cross-sectional area of cardiomyocytes were significantly lower in Rheb-/- 8 days after birth. Next, to examine the role of Rheb-mTORC1 pathway in pathological hypertrophy, we generated conditional Rheb-/- mice by crossing Rhebflox/flox mice with Mer-Cre-Mer transgenic mice. Cardiac pressure overload was induced by means of transverse aortic constriction (TAC), and mice were sacrificed one week after TAC. The heart weight to tibia length ratio and the cross-sectional area of cardiomyocytes were significantly increased in both TAC-operated control and conditional Rheb-/- group compared to that of corresponding sham-operated group. Taken together, Rheb is not essential in pathological hypertrophy, but is essentilal in cardiac developmental hypertrophy in the post-neonatal period.
- © 2012 by American Heart Association, Inc.