Abstract P216: PRAS40 Is a Critical Regulator of Cardiomyocyte Growth
Background: Proline-rich Akt substrate of 40 kDa (PRAS40) is a component of the mammalian target of rapamycin complex (mTORC) 1. Whereas, PRAS40 was originally characterized as substrate for PKB/Akt, subsequent studies identified PRAS40 both as inhibitor and substrate of mTORC1. These studies identify PRAS40 as a negative regulator of mTORC1 activity and cell growth. Phosphorylation of PRAS40 by AKT, which results in dissociation of PRAS40 from mTORC1, relieves the inhibitory constraint on mTORC1. The physiological role and pathophysiological function of PRAS40 in the heart is unknown.
Methods and Results PRAS40 is expressed in cardiomyocytes and highly phosphorylated in embryonic and neonatal hearts. PRAS40 phosphorylation and expression is decreased in adult cardiomyocytes. Pathological challenge in mice induced phosphorylation of PRAS40 in the border zone after myocardial infarction and globally after transaortic constriction. Subcellular, phosphorylated PRAS40 is localized in the cytoplasma after pathological challenge, whereas stimulation with Insulin or IGF1 induced nuclear localization of PRAS40. Adenoviral mediated overexpression of PRAS40 completely blocks pathological hypertrophy after stimulation with phenylephrine as well as physiological growth after stimulation with IGF1 or Insulin. Molecular, mTORC1 activity was significantly reduced after PRAS40 overexpression. Conversely, silencing of PRAS40 resulted in significant increased mTORC1 activity. Gain and loss of function studies of PRAS40 in vivo will be performed to test the therapeutically potential of PRAS40.
Conclusion PRAS40 is a novel regulator of cardiomyocyte growth. Manipulation the activity or expression of PRAS40 could represent a novel therapeutic target to treat cardiac diseases.
- © 2011 by American Heart Association, Inc.