Targeting Myocardial Fibrosis-A Magic Pill in Cardiovascular Medicine?

Abstract

Fibrosis, characterized by an excessive accumulation of extracellular matrix, has long been seen as an adaptive process that contributes to tissue healing and regeneration. More recently, however, cardiac fibrosis has been shown to be a central element in many cardiovascular diseases (CVDs), contributing to the alteration of cardiac electrical and mechanical functions in a wide range of clinical settings. This paper aims to provide a comprehensive review of cardiac fibrosis, with a focus on the main pathophysiological pathways involved in its onset and progression, its role in various cardiovascular conditions, and on the potential of currently available and emerging therapeutic strategies to counteract the development and/or progression of fibrosis in CVDs. We also emphasize a number of questions that remain to be answered, and we identify hotspots for future research.

Keywords: antifibrotic strategies; cardiac fibrosis; cardiovascular diseases; fibrosis pathways; therapeutic strategies.

Figure 1

Interactions between different cardiac cells involved in the development of cardiac fibrosis. Cardiac cells (i.e., cardiac myocytes, macrophages, mast cells, lymphocytes, endothelial cells, and fibroblasts) regulate cardiac fibrosis in a coordinated manner. In the presence of cardiac injury, these cells release inflammatory mediators that stimulate fibroblast-to-myofibroblast differentiation, contributing to the development of fibrotic tissue. Transforming growth factor-beta (TGF-β) is among the most relevant of these profibrotic mediators. “+” designates a stimulatory effect.

Figure 2

Pathways related to angiotensin II and their contribution to myocardial fibrosis. The figure describes the formation of angiotensin II (left part of the figure) and the consequent activation, via AT1 receptors, of numerous inflammatory and profibrotic pathways (middle part of the figure), which will eventually lead to profibrotic cardiac fibroblast and myocyte changes (right part of the figure). Myocyte hypertrophy has been shown to promote fibrosis by stimulating fibroblast activation via a complex network of downstream signal transduction pathways and by increasing the production of growth factors. “↑” designates an increase in profibrotic cardiac fibroblast and myocyte changes. ACE—angiotensin-converting enzyme; AKT—protein kinase B; AT1—angiotensin II type 1 receptor; ECM—extracellular matrix; ERK—extracellular signal-regulated kinase; MAPK—mitogen-activated protein kinase; MMPs—matrix metalloproteinases; TAK1—TGF-β-activated kinase 1; TGF-β—transforming growth factor-beta.

Figure 3

G protein-coupled receptors-related pathways and β-arrestin-mediated events. G-protein coupled receptors are transmembrane proteins embedded in the membrane of cardiomyocytes, fibroblasts, endothelial, and vascular smooth muscle cells that convert extracellular signals into intracellular responses. When activated by agonists (e.g., epinephrine, peptide hormones), inactive G protein heterotrimers dissociate into separate, active Gα and Gβγ subunits that differentially control downstream signal transduction. Intracellular mediators such as protein kinases A and C resulted from this process further phosphorylate the receptors and activate β-arrestin-mediated signaling, activating subsequent signaling cascades involved in cardiac fibrotic disease. AC—adenylyl cyclase; AKT—protein kinase B; cAMP—cyclic adenosine monophosphate; DAG—diacylglycerol; EGFR—epidermal growth factor receptor; IP3—inositol trisphosphate; MAPK—mitogen-activated protein kinase; PI3K—phosphoinositide 3-kinase; PIP2—phosphatidylinositol-4,5-bisphosphate; PKA—protein kinase A; PLC—phospholipase C; PKC—protein kinase C.

Figure 4

Transforming growth factor beta-related pathways and their contribution to myocardial fibrosis. Paracrine factors in fibroblasts, the most important of which is transforming growth factor-beta, induce profibrotic responses in cardiomyocytes. The activation of type I and II transforming growth factor-beta receptors regulates cell phenotypes by activating Smad- and non-Smad-related signaling pathways that eventually result in cardiomyocyte apoptosis and hypertrophy. MAPK—mitogen-activated protein kinase; TAK1—transforming growth factor-beta-activated kinase 1; TβIR—transforming growth factor-beta receptor type I; TβIIR—transforming growth factor-beta receptor type II.