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β 3 Integrin‐mediated ubiquitination activates survival signaling during myocardial hypertrophy
Author(s) -
Johnston Rebecca K.,
Balasubramanian Sundaravadivel,
Kasiganesan Harinath,
Baicu Catalin F.,
Zile Michael R.,
Kuppuswamy Dhandapani
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-127480
Subject(s) - integrin , ubiquitin ligase , muscle hypertrophy , ubiquitin , mechanotransduction , microbiology and biotechnology , pressure overload , medicine , signal transduction , fibronectin , endocrinology , chemistry , biology , receptor , extracellular matrix , biochemistry , cardiac hypertrophy , gene
Identifying the molecular mechanisms activated in compensatory hypertrophy and absent during decompensation will provide molecular targets for prevention of heart failure. We have previously shown enhanced ubiquitination (Ub) during the early growth period of pressure overload (PO) hypertrophy near intercalated discs of cardiomyocytes, where integrins are important for mechanotransduction. In this study, we tested the role of integrins upstream of Ub, whether enhanced Ub contributes to survival signaling in early PO, and if loss of this mechanism could lead to decreased ventricular function. The study used a β 3 integrin ( –/– ) mouse and a wild‐type mouse as a control for in vivo PO by transverse aortic constriction (TAC) and for cultured cardiomyocytes in vitro , stimulated with the integrin‐activating peptide RGD. We demonstrate β 3 integrin mediates transient Ub of targeted proteins during PO hypertrophy, which is necessary for cardiomyocyte survival and to maintain ventricular function. Prosurvival signaling proceeds by initiation of NF‐KB transcription of the E3 ligase, cIAP1. In PO α 3 –/– mice, absence of this mechanism correlates with increased TUNEL staining and decreased ventricular mass and function by 4 wk. This is the first study to show that a β 3 integrin/Ub/NF‐KB pathway contributes to compensatory hypertrophic growth.— Johnston, R. K., Balasubramanian, S., Kasiganesan, H., Baicu, C. F., Zile, M. R., Kuppuswamy, D. β3Integrin‐mediated ubiquitination activates survival signaling during myocardial hypertrophy. FASEBJ. 23, 2759–2771 (2009)