Attenuation of cardiac fibrosis via CBP/P300 bromodomain inhibition

Project: Research

Investigators

  • Marcello Rubino (PI)

Description

Cardiac fibrosis is defined as the existence of excess collagen-rich fibrotic tissue in the myocardium, which leads to adverse outcomes such as fatal arrhythmias, and heart failure via abnormal muscle relaxation and contraction. Clinical trials that have been performed with numerous therapies aimed at reversing cardiac fibrosis in a variety disease states have largely been unsuccessful. Thus, cardiac fibrosis remains a major unmet medical need, and the elucidation of novel mechanisms involved in fibrogenesis in the heart is required for development of new therapies for this prevalent and deadly process. We performed a high throughput phenotypic screening to test the antifibrotic effect of 1907 unique compounds in rat and human myofibroblasts (NRK9F and NHFL cell lines). We found 33 compounds with an anti-fibrotic effect both in rat and in human. We are focusing on PF-CBP1, an inhibitor of Cyclic AMP response element binding protein (CREB)-binding protein (CBP) and E1A interacting protein of 300 kDa (p300) bromodomain. CBP/p300 are co-activators that regulate cellular events like cardiac fibrosis, through their acetyltransferase activity. Recent articles showed that CBP/p300 bromodomain inhibitors regulate global H3K27Ac levels, affecting specific enhancers and super-enhancers transcriptional gene regulation. We started to characterize the specific anti-fibrotic role of the CBP/p300 bromodomain inhibitors PF-CBP1. We found that the compound induce the downregulation of the fibrotic genes ACTA2, Periostin and MCP1 and the modulation of inflammatory genes like IL-6 in mouse and rat cardiac myofibroblasts. We are studying CBP/p300 bromodomain mechanisms of action: we discovered that his inhibition, downregulates some of the pro-fibrotic lncRNAs and eRNAs and it decrease the enrichment of H3K27Ac deposition on the modulated regulatiory region. Furthermore, we confirmed PF-CBP1 antifibrotic effect in activated human fibroblasts. We believe that this high throughput phenotypic screening would be a really useful and powerful tool to found new and potential therapeutic drugs against cardiac fibrosis and diseases.
Award amount$139,336.00
Award date01/01/2020
Program typePostdoctoral Fellowship
Award ID20POST35210627
Effective start/end date01/01/202012/31/2021
StatusActive