Abstract 348: p38γ and δ Promote Heart Hypertrophy by Targeting the Mtor-inhibitory Protein Deptor for Degradation
| Autor: | Bárbara González-Terán, Juan A López, Elena Rodríguez, Luis Leiva, Sara Martínez-Martínez, Luis J Jiménez-Borreguero, Juan M Redondo, Jesús Vazquez, Guadalupe Sabio |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Circulation Research. 117 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Disrupted organ growth underlies the development of several diseases. Whereas the fetal heart grows mainly through proliferation, the postnatal heart grows through hypertrophy. Hypertrophy is also activated in the adult heart as a compensatory response to stress, but chronic ventricular hypertrophy leads to heart failure. The molecular mechanisms underlying ventricular hypertrophy are unknown. We show that cardiac expression and activation of p38γ and p38δ increases during postnatal development and these kinases are activated by the hypertrophy-inducing stress stimuli angiotensin II and phenylephrine. p38γ and p38δ promote cardiac hypertrophy by phosphorylating the mTORC1 and mTORC2 inhibitor DEPTOR, promoting its degradation and thereby activating mTORC1 and mTORC2. Hearts from mice lacking one or both kinases were below-normal size, had high levels of DEPTOR and consequently low activity of the mTOR pathway, and reduced protein synthesis. The mTOR inhibitor, rapamycin, equalized heart weight in wild-type and p38γ/δ-/- mice. Moreover, p38γ/δ-/- mice were protected against pathological ventricular hypertrophy, establishing p38γ/δ as key regulators of this process. |
| Databáze: | OpenAIRE |
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