Focal adhesion kinase governs cardiac concentric hypertrophic growth by activating the AKT and mTOR pathways

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art_STRAUSS_Focal_adhesion_kinase_governs_cardiac_concentric_hypertrophic_growth_2012.PDF (1.23 MB)
Citações na Scopus
52
Tipo de produção
article
Data de publicação
2012
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Autores
CLEMENTE, C. F. M. Z.
XAVIER-NETO, J.
COSTA, A. P. Dalla
CONSONNI, S. R.
ANTUNES, J. E.
ROCCO, S. A.
PEREIRA, M. B.
JUDICE, C. C.
JOAZEIRO, P. P.
Citação
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, v.52, n.2, Special Issue, p.493-501, 2012
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
The heart responds to sustained overload by hypertrophic growth in which the myocytes distinctly thicken or elongate on increases in systolic or diastolic stress. Though potentially adaptive, hypertrophy itself may predispose to cardiac dysfunction in pathological settings. The mechanisms underlying the diverse morphology and outcomes of hypertrophy are uncertain. Here we used a focal adhesion kinase (FAK) cardiac-specific transgenic mice model (FAK-Tg) to explore the function of this non-receptor tyrosine kinase on the regulation of myocyte growth. FAK-Tg mice displayed a phenocopy of concentric cardiac hypertrophy, reflecting the relative thickening of the individual myocytes. Moreover, FAK-Tg mice showed structural, functional and molecular features of a compensated hypertrophic growth, and preserved responses to chronic pressure overload. Mechanistically, FAK overexpression resulted in enhanced myocardial FAK activity, which was proven by treatment with a selective FAK inhibitor to be required for the cardiac hypertrophy in this model. Our results indicate that upregulation of FAK does not affect the activity of Src/ERK1/2 pathway, but stimulated signaling by a cascade that encompasses PI3K, AKT, mTOR, S6K and rpS6. Moreover, inhibition of the mTOR complex by rapamycin extinguished the cardiac hypertrophy of the transgenic FAK mice. These findings uncover a unique role for FAK in regulating the signaling mechanisms that governs the selective myocyte growth in width, likely controlling the activity of PI3K/AKT/mTOR pathway, and suggest that FAK activation could be important for the adaptive response to increases in cardiac afterload. This article is part of a Special Issue entitled ""Local Signaling in Myocytes"".
Palavras-chave
Cardiac myocytes, Cardiac failure, Mechanotransduction, Signal transduction, Transgenic mice
URI
https://observatorio.fm.usp.br/handle/OPI/1618
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Coleções
Artigos e Materiais de Revistas Científicas - LIM/24
Artigos e Materiais de Revistas Científicas - HC/ICESP