Therapeutic targets for cardiac fibrosis: from old school to next-gen
Joshua G. Travers, Charles A. Tharp, Marcello Rubino, Timothy A. McKinsey
Joshua G. Travers, Charles A. Tharp, Marcello Rubino, Timothy A. McKinsey
View: Text | PDF
Review Series

Therapeutic targets for cardiac fibrosis: from old school to next-gen

Abstract

Cardiovascular diseases remain the leading cause of death worldwide, with pathological fibrotic remodeling mediated by activated cardiac myofibroblasts representing a unifying theme across etiologies. Despite the profound contributions of myocardial fibrosis to cardiac dysfunction and heart failure, there currently exist limited clinical interventions that effectively target the cardiac fibroblast and its role in fibrotic tissue deposition. Exploration of novel strategies designed to mitigate or reverse myofibroblast activation and cardiac fibrosis will likely yield powerful therapeutic approaches for the treatment of multiple diseases of the heart, including heart failure with preserved or reduced ejection fraction, acute coronary syndrome, and cardiovascular disease linked to type 2 diabetes. In this Review, we provide an overview of classical regulators of cardiac fibrosis and highlight emerging, next-generation epigenetic regulatory targets that have the potential to revolutionize treatment of the expanding cardiovascular disease patient population.

Authors

Joshua G. Travers, Charles A. Tharp, Marcello Rubino, Timothy A. McKinsey

×

Figure 3

Discovering the next generation of antifibrotic epigenetic inhibitors for the heart.

Options: View larger image (or click on image) Download as PowerPoint
Discovering the next generation of antifibrotic epigenetic inhibitors fo...
Proposed model for expeditiously uncovering novel epigenetics-based therapeutics targeting fibroblast activation and cardiac fibrosis. The recent development of highly selective and potent inhibitors of myriad epigenetic targets has laid a strong foundation for therapeutic investigation using ex vivo, imaging-based phenotypic screening and subsequent exploration in in vivo models of cardiac fibrosis and HF. Given the existence of “hidden fibrosis,” histological assessment of fibrotic remodeling of the heart should be complemented with techniques such as ECM mass spectrometry, atomic force microscopy (AFM), and single-cell RNA sequencing. We envision that these approaches will allow desperately needed therapeutic strategies targeting myofibroblast activation and fibrotic remodeling to finally bridge the gap to the clinical realm.