Abstract 20724: The Absence of the Chromatin Reader Brd2 Decreases Heart Function and Increases Mortality After Pressure Overload

    loading  Checking for direct PDF access through Ovid

Abstract

Introduction: Mechanical stress is a known risk factor that triggers pathologic changes of the heart. Such stress response can be implemented by epigenetic mechanisms like histone modifications. The Bromo- and extraterminal domain (BET) proteins are chromatin readers that recognize histone acetylation finally leading to transcriptional changes. Recently, the BET inhibitor JQ1 was shown to displace those readers from chromatin and to preserve heart function when applied in a mouse transverse aortic constriction (TAC) induced pressure-overload model. Suggesting a major role for BET proteins in the development of heart failure, BET inhibition might be an interesting therapeutic approach.

Hypothesis: In our study we challenged the hypothesis that particular BET proteins play a substantial role in the development and progression of heart failure.

Methods: We analyzed BET expression after stress induction by RNA sequencing. Using conditional knock out mice and echocardiography, we investigated whether the absence of the BET member Brd2 from cardiomyocytes has an impact on heart function and survival after TAC.

Results: Transcriptome analysis showed no difference in BET expression between TAC and control mice 1 and 8 weeks after surgery (n=5). No significant differences were observed between Brd2 knock out and wildtype mice in terms of cardiac stress marker expression, left ventricular end diastolic diameter and wall thickness 10 weeks after TAC. But in comparison to wildtype mice, the absence of BRD2 reduced mean ejection fraction by 18 to 18.5% ±1.84SEM (p=0.0018, n=10) 10 weeks after TAC and lead to 58% higher mortality with a survival rate of 8,45% ±5.22SEM (p=0.0129, n=34) 120 days after TAC.

Conclusions: We conclude that Brd2 does not promote heart failure but might be necessary to compensate for pressure overload as the cardiomyocyte specific Brd2 knock out does not resemble cardio protective properties of BET inhibition but even accelerates progression of heart failure. Due to this controversy, we also think that BET proteins might have adverse functions in the heart. To fully explore the therapeutic potential of BET inhibition, future studies should focus on the remaining BET members Brd3 and Brd4 and more selective alternatives to JQ1.

Related Topics

    loading  Loading Related Articles