Cardiac Fibrosis: The Fibroblast Awakens

Abstract

Myocardial fibrosis is a significant global health problem associated with nearly all forms of heart disease. Cardiac fibroblasts comprise an essential cell type in the heart that is responsible for the homeostasis of the extracellular matrix; however, upon injury, these cells transform to a myofibroblast phenotype and contribute to cardiac fibrosis. This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy and apoptosis, and ultimately leads to the progression to heart failure. Despite the critical importance of fibrosis in cardiovascular disease, our limited understanding of the cardiac fibroblast impedes the development of potential therapies that effectively target this cell type and its pathological contribution to disease progression. This review summarizes current knowledge regarding the origins and roles of fibroblasts, mediators and signaling pathways known to influence fibroblast function after myocardial injury, as well as novel therapeutic strategies under investigation to attenuate cardiac fibrosis.

Keywords: disease progression; extracellular matrix; fibroblasts; fibrosis; heart failure; therapeutics.

Figure 1. Characteristics and Functions of Activated Cardiac MFs

Cardiac fibroblasts respond to pathologic stress and environmental stimuli by transforming into MFs that (1) express elevated levels of various pro-inflammatory and pro-fibrotic factors that directly contribute to inflammatory cell infiltration and fibroblast proliferation, (2) secrete high levels of matrix metalloproteinases and other ECM degrading enzymes that facilitate fibroblast migration and (3) contribute to the deposition of collagen and other ECM proteins leading to scar formation. While this adaptive fibrotic scar tissue maintains the structural integrity and pressure generating capacity of the heart, MF persistence eventually leads to the development of adverse changes in ventricular structure and compliance, leading to the progression to heart failure.

Figure 2. Proposed Sources of Cardiac MFs

The source(s) of activated CFs that accumulate in response to various pathological insults remains under active investigation. Mounting evidence suggests that activated MFs in the fibrotic heart derive from the proliferation and activation of resident fibroblasts, as these cells are remarkably sensitive to pathologic insult and represent a feasible source of matrix-producing cells during cardiac fibrosis. Numerous additional precursors to the fibroblast population in the injured heart have been proposed; these include endothelial and epicardial cells, through EMT and EndMT, respectively, hematopoietic bone marrow-derived cells, perivascular cells and fibrocytes. While supporting evidence exists for cellular sources of activated fibroblasts denoted by question marks, controversy remains regarding the functional contribution of these cell types to the cardiac MF population. Biomarkers with greater specificity will be required to fully characterize the pathophysiologic relevance of these cell types in the cardiac fibrotic response, which will enable potential targeting for anti-fibrotic therapies.

Figure 3. Selection of Signaling Pathways Regulating MF Activation and Potential Therapeutic Targets for Cardiac Fibrosis

Numerous signaling pathways have been implicated in the activation of cardiac fibroblasts and the induction of pathological remodeling; targeting these signals is of intense scientific interest toward development of novel therapeutic strategies. Cardiac injury promotes the activation of receptors such as the β-AR, ALK5, AT1R, ETR, TRPC6 and Integrins, which induces pathologic signaling through numerous mediators, leading to the transcription of factors that regulate MF activation and fibrotic remodeling. Proposed antifibrotic therapeutic targets are marked with a red X. (β-AR: β-adrenergic receptor, AC: adenylate cyclase, TRPC6: transient receptor potential channel C6, AT1R: type 1 angiotensin II receptor, ETR: endothelin receptor: TGF-β: transforming growth factor β, LTBP: latent TGF-β binding protein, ALK5: activin receptor-like kinase 5 / TGF-β receptor, GRK2: g protein-coupled receptor kinase 2, ERK1/2: extracellular regulated kinase 1/2, MEK1: mitogen activated protein kinase kinase 1, NFAT: nuclear factor of activated T-cells, MRTF: myocardin-related transcription factor, TAK1: TGF-β – activated kinase 1, JNK: c-JUN N-terminal kinase, PI3K: phosphoinositide 3-kinase).