A Profibrotic Signaling Nexus
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Article, see p 549
Fibrosis of the heart is driven by the reprogramming of resident fibroblasts into contractile myofibroblasts that express high levels of extracellular matrix. Cardiac fibrosis may be beneficial, replenishing regions of myocyte loss with a structural scar after infarction, or maladaptive, involving excess extracellular matrix deposition in response to long-standing stress. Uncontrolled cardiac fibrosis can have dire consequences. For example, fibrosis increases the passive stiffness of the myocardium, contributing to diastolic dysfunction, and disrupts electric conduction in the heart, causing arrhythmias and sudden cardiac death. Clinical trials aimed at treating heart failure with preserved ejection fraction, in part by blocking cardiac fibrosis, have mainly centered on inhibiting components of the renin-angiotensin-aldosterone system and have largely been unsuccessful.1 As such, cardiac fibrosis is a major unmet medical need, and the discovery of new mechanisms that control fibrosis in the heart is required for development of innovative therapies for this prominent and devastating process.
Transforming growth factor (TGF)-β is a cytokine that controls fibrosis across organ systems. Binding of TGF-β to its cell surface receptor triggers phosphorylation and nuclear translocation of SMAD transcription factors, which bind regulatory elements in a variety of profibrotic genes. An article published by Molkentin et al in this issue of Circulation2 defines a crucial role for noncanonical, SMAD-independent TGF-β signaling in the control of cardiac fibrosis. In a tour-de-force of elegant genetic gain- and loss-of-function studies, the authors demonstrate that the mitogen-activated protein kinase p38α is a nodal effector of profibrotic TGF-β signaling in the heart. These findings were reported in this seminal article:
p38α (Mapk14 gene) deletion in cultured fibroblasts blocked differentiation of the cells into α-smooth muscle actin-positive myofibroblasts in response to TGF-β, angiotensin II, or cyclic stretching.
The block to myofibroblast differentiation in cultured fibroblasts lacking p38α could be …