In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 109, No. suppl_1 ( 2011-12-09)
Abstract:
Rheb (Ras homologue enriched in brain) is a major activator of mTOR. Rheb-mTOR pathway is a critical mechanism for maintenance of homeostasis, cell growth and stress response by regulating both protein synthesis and degradation. In this study, we attempted to clarify the role of Rheb-mTOR pathway in the heart using cardiac-specific Rheb-deficient mice (Rheb −/− ). We generated floxed Rheb mice and crossed them with transgenic mice expressing Cre recombinase in cardiac-specific mannner to generate Rheb −/− . Rheb −/− were born in Mendelian ratio, but they started to die 8 days after birth and all of them had died until 10 days after birth. Echocardiographic analysis revealed that chamber dimension and contractile function of Rheb −/− were indistinguishable from those of control mice (Rheb +/+ ) 5 days after birth. However, Rheb −/− exhibited cardiac dilatation and reduced contractility 8 days after birth (LV end diastolic dimension, Rheb −/− : 2.5±0.2 mm vs. Rheb +/+ : 2.1±0.2 mm, p 〈 0.01, fractional shortening, Rheb −/− : 19.7 ± 9.7 % vs. Rheb +/+ : 48.6 ± 8.8 %, p 〈 0.01). These suggest that Rheb −/− died of cardiac dysfunction and heart failure. Heart weight and cross-sectional area of cardiomyocytes were significantly lower in Rheb −/− 8 days after birth. Electron microscopic analysis revealed that the area of sarcomere was significantly lower in Rheb −/− cardiomyocytes. Expressions of sarcomeric proteins, such as myosin heavy chain, actin or desmin, were decreased in Rheb −/− , while the mRNA expression of desmin was significantly increased in Rheb −/− . Thus impairment of cardiomyocyte growth observed in Rheb −/− could be due to either increased degradation or decreased translation. Although autophagic activity was enhanced in Rheb −/− heart, ablation of Atg5, an essential molecule for autophagy, could not prevent premature death of Rheb −/− . On the other hand, polysome analysis revealed that the mRNA translation activity had decreased in Rheb −/− heart compared with Rheb +/+ . Thus, we concluded that Rheb-mTOR pathway in the heart is essential to regulate mRNA translation activity and protein synthesis, thereby to cardiomyocyte growth in neonatal period.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/res.109.suppl_1.AP111
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2011
detail.hit.zdb_id:
1467838-X
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