title: Angiotensin II-induced cardiomyocyte hypertrophy in vitro is TAK1-dependent and Smad2/3-independent.
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-β1 (TGFβ1), which is also implicated in the cardiac hypertrophic response and can stimulate activation of Smad2/3 as well as TGFβ-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 TGFβ1 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 TGFβ type I receptor inhibitor, SB431542, were used to investigate the role of downstream mediators of TGFβ signaling in the hypertrophic response. Our data revealed that TGFβ1 stimulation leads to cardiomyocyte hypertrophic phenotypes that were indistinguishable from those occurring in response to Ang II. In addition, inhibition of the TGFβ1 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.
authors.affiliation: Institute of Human Genetics, Centre for Life, Newcastle University, Newcastle, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Watkins
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Borthwick
authors.forename: Rachael
authors.initials: R
authors.lastname: Oakenfull
authors.forename: Andrew
authors.initials: A
authors.lastname: Robson
authors.forename: Helen M
authors.initials: HM
authors.lastname: Arthur
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000378:metabolism; D002478:Cells, Cultured; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000804:Angiotensin II; D020930:MAP Kinase Kinase Kinases; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D000099151:MAP Kinase Kinase Kinase 7