Key result
SMAD4 overexpression increases apoptosis ~16% and reduces protein synthesis in phenylephrine-stimulated rat cardiomyocytes.
SMAD4 triggers the transition from hypertrophy to apoptosis in ventricular cardiomyocytes, providing a potential molecular mechanism for negative remodeling and heart failure progression.
May inform SMAD4's role in cardiomyocyte fate decisions; hypothesis-generating for heart failure remodeling, requires human validation before any clinical consideration.
Heart failure development goes along with a transition from hypertrophic growth to apoptosis induction. In adult cardiomyocytes SMAD proteins are only activated under apoptotic, but not under hypertrophic conditions and are increased at the transition to heart failure. Therefore, SMADs could be candidates that turn the balance from hypertrophic growth to apoptosis resulting in heart failure development. To test this hypothesis we infected isolated rat ventricular cardiomyocytes with adenovirus encoding SMAD4 (AdSMAD4) and investigated the impact of SMAD4 overexpression on the development of apoptosis and hypertrophy under stimulation with phenylephrine (PE). Infection of cardiomyocytes with AdSMAD4 significantly enhanced SMAD-binding activity while apoptosis after 24 and 36 h infection did not rise. But when SMAD4 overexpressing cardiomyocytes were incubated with PE (10 microM), the number of apoptotic cells increased (Ctrl: 94.97 +/- 6.91%; PE: 102.48 +/- 4.78% vs. AdSMAD4 + PE: 118.64 +/- 3.28%). Furthermore expression of caspase 3 as well as bax/bcl2 ratio increased in SMAD4 overexpressing, PE-stimulated cardiomyocytes. In addition, the effects of SMAD4 overexpression on PE-induced hypertrophic growth were analyzed. Protein synthesis 36 h after AdSMAD4 infection was comparable to control cells, whereas the increase in protein synthesis stimulated by phyenylephrine was significantly reduced in SMAD4 overexpressing cells (134.28 +/- 10.02% vs. 100.57 +/- 8.86%). SMAD4 triggers the transition from hypertrophy to apoptosis in ventricular cardiomyocytes. Since SMADs are increased under several pathophysiological conditions in the heart, it can be assumed that it triggers apoptosis induction and therefore contributes to negative remodeling and heart failure progression.
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Heger et al. (2009) studied Heart failure, hypertrophy, and apoptosis. Adenovirus encoding SMAD4 (AdSMAD4) with phenylephrine (PE) vs. Control or PE alone was evaluated on Number of apoptotic cells. In isolated rat ventricular cardiomyocytes, SMAD4 overexpression combined with phenylephrine increased apoptosis (118.64% vs 102.48% with PE alone) and reduced PE-stimulated protein synthesis.
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