Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmia

Abstract

The importance of fibrosis in organ pathology and dysfunction appears to be increasingly relevant to a variety of distinct diseases. In particular, a number of different cardiac pathologies seem to be caused by a common fibrotic process. Within the heart, this fibrosis is thought to be partially mediated by transforming growth factor-beta1 (TGF-beta1), a potent stimulator of collagen-producing cardiac fibroblasts. Previously, TGF-beta1 had been implicated solely as a modulator of the myocardial remodelling seen after infarction. However, recent studies indicate that dilated, ischaemic and hypertrophic cardiomyopathies are all associated with raised levels of TGF-beta1. In fact, the pathogenic effects of TGF-beta1 have now been suggested to play a major role in valvular disease and arrhythmia, particularly atrial fibrillation. Thus far, medical therapy targeting TGF-beta1 has shown promise in a multitude of heart diseases. These therapies provide great hope, not only for treatment of symptoms but also for prevention of cardiac pathology as well. As is stated in the introduction, most reviews have focused on the effects of cytokines in remodelling after myocardial infarction. This article attempts to underline the significance of TGF-beta1 not only in the post-ischaemic setting, but also in dilated and hypertrophic cardiomyopathies, valvular diseases and arrhythmias (focusing on atrial fibrillation). It also aims to show that TGF-beta1 is an appropriate target for therapy in a variety of cardiovascular diseases.

Figures

Figure 1

The TGF-β1–Smad pathway. (1) Initiation of the pathway begins after TGF-β1 is up-regulated by angiotensin II. (2) Once in the extracellular space, TGF-β1 binds to a dimerized receptor, consisting of TGF-β1receptor 1 (TGF-β1R1) and TGF-β1 receptor 2 (TGF-β1R2), found on the surface of fibroblasts and myofibroblasts. (3) Ligand-receptor binding results in the phosphorylation of Smad2. Smad6, an inhibitory protein in the Smad family, impedes this phosphorylation. (4) Once phosphorylated, Smad2 combines with Smad 3 and Smad 4 to form a Smad complex that translocates across the nuclear membrane. Smad7, another inhibitory Smad protein, interrupts Smad complex formation. (5) Within the nucleus, the Smad complex binds to Smad-binding elements found in the regulatory regions of genes encoding extracellular matrix proteins. This final step promotes the expression of collagen type I and type III in the heart and results in fibrosis.

Figure 2

The TGF–TAK1 pathway. (1) Initiation of the pathway begins when TGF- β1 binds to the dimerized TGF- β1 receptor 1 (TGF- β1R1) – TGF- β1 receptor 2 (TGF- β1R2) complex. (2) Ligand-receptor binding results in the intracellular activation of TAK1. (3) Activated TAK1 mediates p38 phosphorylation. (4) After being phosphorylated, p38 promotes phosphorylation of ATF-2. (5) The Smad complex then combines with ATF-2 resulting in augmented protein synthesis.

Figure 3

A histological section of the pulmonary veins at the region of the ostium. Disorganized bundles of the myocardial sleeve extending from the left atrium are surrounded by fibrotic connective tissue. Provided by courtesy of Ivana Kholova, MD.