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-b1 (TGFb1), which is also implicated in the cardiac hypertrophic response and can stimulate activation of Smad2/3 as well as TGFb-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 TGFb1 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 TGFb type I receptor inhibitor, SB431542, were used to investigate the role of downstream mediators of TGFb signaling in the hypertrophic response. Our data revealed that TGFb1 stimulation leads to cardiomyocyte hypertrophic phenotypes that were indistinguishable from those occurring in response to Ang II. In addition, inhibition of the TGFb1 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.

Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-β signalling

“…Smad2 activation was induced by AngII in isolated CFs, as we demonstrated in Figure 7(A) and in our previous study [29]. AngII-induced myocyte hypertrophy is not only exclusively dependent upon endogenous TGF- β but also is TAK1-dependent and Smad2/3-independent in vitro [45]. Matsumoto-Ida et al [46] showed that TAK1 protein is exclusively localized in myocytes in the non-infarct zone after experimental MI and thus postulated that the activation of the TGF- β 1/TAK1/p38 MAPK pathway in myocyte is involved in ventricular remodelling.…”

Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy

“…41 Activation of TAK1 was well-documented to pivotally induce cardiac hypertrophic growth at baseline or in response to pressure overload, [41][42][43][44] whereas a recent study reported that cardiacspecific depletion of TAK1 induced cell death and cardiac dysfunction.…”

“…TAK1 is a member of the MEKK family central to many critical physiological processes 40 and is designated as a pivotal strategic point involved in the development of cardiac hypertrophy. 41 Activation of TAK1 was well-documented to pivotally induce cardiac hypertrophic growth at baseline or in response to pressure overload, [41][42][43][44] whereas a recent study reported that cardiacspecific depletion of TAK1 induced cell death and cardiac dysfunction. 45 Such discrepancy may be reconciled by the dual role of TAK1 in the regulation of myocyte survival and hypertrophy.…”

The Renin-Angiotensin-Aldosterone System in Vascular Inflammation and Remodeling

“…The Ang II growth effects, proliferation versus hypertrophy, are dependent on cell type and cell-cycle regulated genes. For example, Ang II exerts hypertrophic effect on cardiomyocytes via TGF β 1 mediated signaling, and blockade of TGF β 1 receptor abrogates Ang II-mediated cardiomyocytes hypertrophy [125]. In myocardial infarction model (MI), ARB, telmisartan, inhibits cardiac remodeling by reducing cardiomyocytes hypertrophy and fibrosis via an anti-inflammatory effect and activation of peroxisome proliferators-activated receptor gamma (PPAR γ ) [126].…”