Abstract 19914: Differential Targeting of Hypertrophic and Anti-Apoptotic Effects of Erk1/2
Introduction: The ERK1/2 cascade mediates both cardiac hypertrophy and cell survival. We previously showed that autophosphorylation at Threonine 188 (T188) is mandatory to transduce the hypertrophic effects of ERK1/2.
Hypothesis: We assessed the hypothesis that ERK1/2 mediates hypertrophic and anti-apoptotic effects via independent mechanisms, which would allow separate targeting of these pathways.
Methods and results: T188 phosphorylation was found in human hypertrophic and failing hearts as well as in heart tissue of mouse models of hypertrophy. The causal role of T188 phosphorylation was revealed in transgenic mice overexpressing an ERK2 mutant that simulated T188 phosphorylation (ERK2T188D) and developed excessive hypertrophy after transverse aortic contriction (TAC) as assessed by measurements of heart weight, myocyte size and left ventricular wall thickness. Vice versa, phosphorylation deficient mutants (ERK2T188S/A) demonstrated an attenuated hypertrophic response after TAC and also in response to angiotensin II and isoproterenol. In all ERKT188 mutant mouse lines the extent of hypertrophy correlated well with the expression of hypertrophic markers (ANP, BNP) and the development of interstitial fibrosis. Even though the phosphorylation state of T188 was sufficient to induce or attenuate hypertrophy, respectively, overall ERK1/2 activity was identical in all ERKT188 mutants as determined by phosphorylation of an ERK1/2 specific substrate (MBP). To investigate whether T188 phosphorylation also affects anti-apoptotic ERK1/2 functions, TUNEL assays were performed. Intriguingly, in all ERKT188 mutants as well as in wild-type mice the amount of TUNEL positive cells was comparable and increased to the same extent after TAC. These findings indicated that T188 phosphorylation regulates the pro-hypertrophic function of ERK1/2, but has no influence on the anti-apoptotic properties of ERK1/2.
Conclusion: In conclusion, these results indicate that T188 phosphorylation of ERK1/2 represents a specific switch mechanism towards hypertrophic signaling. Targeting of T188 phosphorylation allows to attenuate maladaptive, hypertrophic effects of ERK1/2 without affecting anti-apoptotic, i.e. cardioprotective functions of ERK1/2.
- © 2010 by American Heart Association, Inc.