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β₃ Integrin-mediated ubiquitination activates survival signaling during myocardial hypertrophy

Rebecca K. Johnston^*, Sundaravadivel Balasubramanian^*, Harinath Kasiganesan^*, Catalin F. Baicu^*, Michael R. Zile^*, and Dhandapani Kuppuswamy^*,,1

^* Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA; and the

Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina, USA

¹ Correspondence: Gazes Cardiac Research Institute, 114 Doughty Street, Charleston, SC 29425-2221, USA. E-mail: kuppusd{at}musc.edu

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 β₃ 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 β₃ 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-B transcription of the E3 ligase, cIAP1. In PO β₃^–/– 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 β₃ integrin/Ub/NF-B pathway contributes to compensatory hypertrophic growth.—Johnston, R. K., Balasubramanian, S., Kasiganesan, H., Baicu, C. F., Zile, M. R., Kuppuswamy, D. β₃ Integrin-mediated ubiquitination activates survival signaling during myocardial hypertrophy.

Key Words: NF-B • cIAP1 • pressure overload

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