Heart failure (HF), the final clinical manifestation of numerous cardiovascular pathologies, is a devastating disease with poor prognosis. Nearly all etiologies of cardiovascular disease involve pathological myocardial remodeling, characterized by excessive deposition of extracellular matrix proteins by activated cardiac myofibroblasts, which reduces tissue compliance and accelerates HF progression. Acetylation of nucleosomal lysine residues within chromatin represents an important epigenetic regulatory mechanism of gene transcription that is critical to HF pathogenesis. In particular, the acetyl-lysine reader protein BRD4 has been recognized for its significant contributions to the transcription of pro-fibrotic gene programs, along with the development of cardiac dysfunction and remodeling. Functional studies of BRD4 indicate that the extra-terminal (ET) domain mediates transcriptional elongation of pro-fibrotic gene programs via interactions with co-factor proteins; however, the potential for BRD4 ET domain inhibition in the treatment of cardiovascular disease has yet to be elucidated. Utilizing innovative peptide inhibitors, the proposed studies will investigate the therapeutic potential of BRD4 ET domain inhibition in primary cardiac fibroblasts and a murine model of HF.
The first aim will test the hypothesis that inhibition of the ET domain of BRD4 will alleviate characteristics of pathological myofibroblast activation in primary mouse and human cardiac fibroblasts, and chromatin immunoprecipitation sequencing will provide mechanistic insight into the potential therapeutic properties of this inhibition.
The second aim will evaluate the cardioprotective properties of these novel BRD4 ET domain inhibitors in a clinically relevant pressure-overload model of HF. Potential salutary properties on cardiac dysfunction will be assessed, along with the evaluation of hypertrophy and fibrotic remodeling by histology and proteomic analysis of the extracellular matrix. Finally, RNA-sequencing will be utilized to determine global gene expression alterations in the myocardium in response to BRD4 ET domain inhibition. Importantly, the proposed work will significantly enhance the applicant's skill sets in primary cell culture, cardiovascular physiology, rodent models of HF, and the investigation of epigenetic mechanisms regulating gene transcription. Together with the mentorship of a renowned expert in cardiovascular epigenetics committed to the development of young scientists, this training will provide a solid foundation for the applicant's development into an independent investigator. Moreover, this innovative approach offers the exciting potential for the development of direly needed novel therapeutic strategies for the treatment of HF.
Heart failure is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance, and despite significant improvements to therapeutic interventions, remains the leading cause of death worldwide. The histone reader protein BRD4 represents an important epigenetic regulator of gene expression that contributes to heart failure pathogenesis, and in particular, the extra-terminal domain of BRD4 is known to mediate transcriptional elongation of pro-fibrotic gene programs. The proposed studies will investigate the previously unexplored therapeutic potential of BRD4 extra-terminal domain inhibition in attenuating pathological gene expression and cardiac remodeling, with the potential for development of novel therapeutics for the treatment of heart failure.
