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Angiotensin II-induced cardiomyocyte hypertrophy in vitro is TAK1-dependent and Smad2/3-independent

Lookup NU author(s): Dr Sarah Watkins, Dr Gillian Borthwick, Rachael Oakenfull, Dr Andrew Robson, Professor Helen Arthur

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Abstract

Cardiac hypertrophy occurs as an adaptation to hypertension but a sustained hypertrophic response can ultimately lead to heart failure. Angiotensin-II (Ang II) is released following hemodynamic overload and stimulates a cardiac hypertrophic response. AngII also increases expression of the regulatory cytokine, transforming growth factor-beta 1 (TGF beta 1), which is also implicated in the cardiac hypertrophic response and can stimulate activation of Smad2/3 as well as TGF beta-activated kinase 1 (TAK1) signaling mediators. To better understand the downstream signaling events in cardiac hypertrophy, we therefore investigated activation of Smad2/3 and TAK1 signaling pathways in response to Ang II and TGF beta 1 using primary neonatal rat cardiomyocytes to model cardiac hypertrophic responses. Small interfering RNA (siRNA) knockdown of Smad 2/3 or TAK1 protein or addition of the TGF beta type I receptor inhibitor, SB431542, were used to investigate the role of downstream mediators of TGF beta signaling in the hypertrophic response. Our data revealed that TGF beta 1 stimulation leads to cardiomyocyte hypertrophic phenotypes that were indistinguishable from those occurring in response to Ang II. In addition, inhibition of the TGF beta 1 type receptor abolished Ang II-induced hypertrophic changes. Furthermore, the hypertrophic response was also prevented following siRNA knockdown of TAK1 protein, but was unaffected by knockdown of Smad2/3 proteins. We conclude that Ang II-induced cardiomyocyte hypertrophy in vitro occurs in a TAK1-dependent, but Smad-independent, manner. Hypertension Research (2012) 35, 393-398; doi: 10.1038/hr.2011.196; published online 10 November 2011


Publication metadata

Author(s): Watkins SJ, Borthwick GM, Oakenfull R, Robson A, Arthur HM

Publication type: Article

Publication status: Published

Journal: Hypertension Research

Year: 2012

Volume: 35

Issue: 4

Pages: 393-398

Print publication date: 01/04/2012

ISSN (print): 0916-9636

ISSN (electronic): 1348-4214

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/hr.2011.196

DOI: 10.1038/hr.2011.196


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