Therapeutic targets for cardiac fibrosis: from old school to next-gen
Joshua G. Travers, … , Marcello Rubino, Timothy A. McKinsey
Joshua G. Travers, … , Marcello Rubino, Timothy A. McKinsey
Published March 1, 2022
Citation Information: J Clin Invest. 2022;132(5):e148554. https://doi.org/10.1172/JCI148554.
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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

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Figure 1

Classical signaling pathways regulating CF activation and approaches for targeting fibrosis of the heart.

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Classical signaling pathways regulating CF activation and approaches for...
Numerous signaling pathways have been implicated in the regulation of CF activation and fibrotic remodeling. Therapeutic targeting of these pathways is of intense scientific and clinical interest. TGF-β stimulation of the TGF-β receptor (TGFβR) drives fibroblast activation canonically through SMAD2/3 activation and nuclear translocation, or non-canonically by inducing TGF-β–activated kinase 1–mediated (TAK1-mediated) phosphorylation of p38. While activation of the β2-adrenergic receptor (β2-AR) is thought to be antifibrotic through induction of cAMP production and activation of exchange protein directly activated by cAMP (EPAC), this signaling can be uncoupled through GPCR kinase 2–mediated (GRK2-mediated) or GRK5-mediated receptor phosphorylation. β3-AR agonists, such as mirabegron, may ameliorate fibroblast activation through yet unknown mechanisms. Angiotensin II (Ang II) mediates fibroblast activation through stimulation of the Ang II type 1 receptor (AT1R), by both promoting TGF-β production and inducing systemic release of the mineralocorticoid aldosterone from the adrenal cortex. Induction of cGMP-dependent protein kinase (PKG), through either B-type natriuretic peptide–mediated (BNP-mediated) activation of type A and B natriuretic peptide receptors (NPR-A/B) or stimulation of soluble guanylate cyclase (sGC) by nitric oxide (NO), has also demonstrated antifibrotic properties. Established and investigatory therapeutic strategies targeting these pathways are listed below. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.