Background: Congestive heart failure (CHF) is a significant health care burden in developed countries, but the molecular events leading from cardiac hypertrophy to CHF are unclear, and preventive therapeutic approaches are limited. We have previously reported that microphthalmia-associated transcription factor (MITF)-mutated mice have diminished cardiac hypertrophy in response to β-adrenergic stimulation and decreased cardiac function, but the molecular mechanisms involved are unknown.
Methods and Results: Gene array analysis of hearts from MITF-mutated mice indicated ErbB2 interacting protein (Erbin), recently demonstrated by our group as an inhibitor of pathologic cardiac hypertrophy, is a candidate target gene for MITF.
MITF acts as an activator of Erbin expression by directly binding two classic E-box elements in the Erbin promoter. Interestingly, cardiac Erbin expression decreased in wild type mice treated with β-adrenergic agonist, but not in MITF-mutated mice. Yeast two-hybrid screening, using MITF as bait, identified an interaction with the cardiac-predominant four-and-a-half LIM domains protein 2 (FHL2), which was confirmed by co-immunoprecipitation in both mouse and human hearts. FHL2 and MITF bind Erbin promoter as a complex. FHL2 association with MITF was increased in heart biopsies of heart failure patients and upon β adrenergic stimulation in mice. Overexpression of FHL2 alone had no effect on Erbin expression, but in the presence of MITF, Erbin expression was decreased.
Conclusion: Our results suggest that MITF-FHL2 interaction acts as signal responsive activator/repressor of Erbin expression during cardiac hypertrophy, and this fine tuning mechanism could be an important regulator of cardiac hypertrophy.
Synopsis:
- We demonstrated in vivo and in vitro that MITF regulates Erbin expression in the heart.
- Under normal conditions MITF activates cardiac Erbin expression.
- MITF represses Erbin expression during cardiac hypertrophy.
- FHL2 associates with MITF and mediates Erbin repression as a complex.
- FHL2 and MITF association is increased in heart failure patients
