A research team led by scientists from the Consortium for Fibrosis Research & Translation (CFReT) at the University of Colorado School of Medicine has identified a potential target for treating heart failure related to fibrosis.
Fibrosis is a wound-healing response after tissue injury or stress. Cardiac fibrosis can cause abnormal stiffening of the heart, contributing to the pathogenesis of heart failure, a condition that afflicts millions of people worldwide. Fibrosis is driven by cells called fibroblasts, which produce excess amounts of extracellular matrix proteins such as collagen, and thereby disrupt operation of the heart.
The CU-led team's study looked at an epigenetic 'reader' protein known as BRD4, showing that it serves a central role in regulating the activation of cardiac fibroblasts. They also found that chemical inhibitors of BRD4 potently block cardiac fibroblast activation, providing a foundation for developing BRD4-targeted small molecule therapies for the treatment of heart failure.
The study was published online last week and appears in the current issue of Circulation Research, the official journal of the American Heart Association and its Council on Basic Cardiovascular Sciences. The cover image for this issue of the journal was chosen from the article. The first authors are Matthew S. Stratton, PhD, and Rushita A. Bagchi, PhD, and the senior author is Timothy A. McKinsey, PhD.
Our study enhances the understanding of the molecular mechanisms by which BRD4 controls pathogenic gene expression in fibroblasts. Together with forthcoming findings, this knowledge should yield a cumulative framework that guides the development of more selective BRD4 inhibitors and offers the potential to provide a therapeutic window for treatment of chronic fibrotic diseases."
Rushita A. Bagchi, postdoctoral fellow in the McKinsey laboratory
Funding for this research comes from the National Institutes of Health, the Canadian Institutes of Health Research, and the American Heart Association. Many of the authors, including McKinsey and Bagchi, are members of the CFReT, a transformational research project created in 2016 with funding from the CU School of Medicine. Eighteen authors are named on the article.
In addition to the article, the journal also features Stratton and Bagchi on its Meet the First Authors page, as well as a podcast interview with Stratton, Bagchi and McKinsey. Stratton was with the McKinsey lab as a postdoctoral fellow until June of 2017, and is now an assistant professor in the Department of Physiology and Cell Biology at The Ohio State University.
Stratton, M.S. et al. (2019) Dynamic Chromatin Targeting of BRD4 Stimulates Cardiac Fibroblast Activation. Circulation Research. doi.org/10.1161/CIRCRESAHA.119.315125.