TGF-β as a therapeutic target in the infarcted and failing heart: cellular mechanisms, challenges, and opportunities

ABSTRACT

Introduction

Myocardial fibrosis accompanies most cardiac conditions and can be reparative or maladaptive. Transforming Growth Factor (TGF)-β is a potent fibrogenic mediator, involved in repair, remodeling, and fibrosis of the injured heart.

Areas covered

This review manuscript discusses the role of TGF-β in heart failure focusing on cellular mechanisms and therapeutic implications. TGF-β is activated in infarcted, remodeling and failing hearts. In addition to its fibrogenic actions, TGF-β has a broad range of effects on cardiomyocytes, immune, and vascular cells that may have both protective and detrimental consequences. TGF-β-mediated effects on macrophages promote anti-inflammatory transition, whereas actions on fibroblasts mediate reparative scar formation and effects on pericytes are involved in maturation of infarct neovessels. On the other hand, TGF-β actions on cardiomyocytes promote adverse remodeling, and prolonged activation of TGF-β signaling in fibroblasts stimulates progression of fibrosis and heart failure.

Expert opinion

Understanding of the cell-specific actions of TGF-β is necessary to design therapeutic strategies in patients with myocardial disease. Moreover, to implement therapeutic interventions in the heterogeneous population of heart failure patients, mechanism-driven classification of both HFrEF and HFpEF patients is needed. Heart failure patients with prolonged or overactive fibrogenic TGF-β responses may benefit from cautious TGF-β inhibition.

KEYWORDS:

• Heart failure
• myocardial infarction
• TGF-β smad
• macrophage
• cardiomyocyte
• vascular cell
• fibroblast
• extracellular matrix

Article highlights

• Transforming growth factor (TGF)-β is induced and activated in infarcted and failing hearts.

• The effects of TGF-β in the infarcted and remodeling heart involve activation of both Smad-mediated and non-Smad pathways and are suppressed by the inhibitory Smad, Smad7.

• In healing infarcts, TGF-β exerts time-dependent reparative and maladaptive actions, suppressing inflammation and stimulating fibroblast activation (thus protecting from rupture), while contributing to late fibrotic remodeling and dysfunction.

• In pressure-overloaded hearts, early TGF-β signaling exerts protective matrix-preserving actions, while prolonged TGF-β activation causes fibrosis and cardiomyocyte dysfunction.

• TGF-β signaling may contribute to the myocardial fibrotic response associated with diabetes and aging.

• Implementation of anti-TGF-β treatment strategies in myocardial infarction and heart failure requires consideration of the cell-specific actions of TGF-β and identification of patients with excessive or prolonged fibrogenic responses.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.