Myocardin-related transcription factor-A: mending a broken heart.

Ventricular remodeling following myocardial infarction (MI) is a complex process driven by the response of both the myocytic and the nonmyocytic components of the heart to dynamic mechanical and neurohumoral stimuli. Despite the advent of reperfusion therapy and the administration of drugs slowing the progression of heart failure, many patients experiencing a MI undergo a progressive decline in ventricular function and deteriorating clinical course.1 Better understanding of the molecular and cellular pathways that influence ventricular remodeling following MI is needed to alter this commonly observed clinical scenario. Although a great deal is understood about the response of the cardiomyocyte to biomechanical stress, much less is understood about the response of the nonmyocytic component of the heart following MI (reviewed elsewhere2). In the acute post-MI setting, collagen accumulation develops in response to cardiomyocyte loss, a process referred to as “replacement fibrosis.” This process is believed to be critical to preserving the structural integrity of the heart. However, clinical studies have revealed that over time the accumulation of collagen and extracellular matrix (ECM) in the heart also contributes to the pathogenesis of ischemic cardiomyopathy and post-MI heart failure.3 As such, elucidation of the molecular and cellular mechanisms regulating fibrosis and scar formation following MI is critical to understanding how cardiac remodeling influences prognosis in patients with ischemic heart disease. The cardiac fibroblast comprises the majority ( 90%) of the nonmyocytic component of the heart.4 Under homeostatic conditions, cardiac fibroblasts synthesize and secrete ECM components including collagens I, III, and IV, fibronectin, laminin, and elastin influencing the systolic and diastolic properties of the heart.2 Following an MI, in response to mechanical and stress-related signals, a subset of cardiac fibroblasts modulate their phenotype and become myofibroblasts, which are distinguished by their spindle-like morphology, high concentration of smooth muscle -actin (SMA), and enhanced secretion of ECM (reviewed elsewhere5). Cardiac myofibroblasts migrate to the infarct zone where they secrete abundant ECM and organize and align collagen fibers, leading to myocardial scar formation. Cardiac myofibroblast conversion and activation occurs in response to biomechanical forces, neurohormones, cytokines, and growth factors, most notably transforming growth factor (TGF).6 In animal models, angiotensin-converting enzyme (ACE) inhibitors, -blockers, and aldosterone antagonists have been shown to decrease myocardial fibrosis in the postinfarct setting.3 This has led some to suggest that the development of therapeutic compounds that block myocardial fibrosis may prevent and/or reverse heart failure in patients with ischemic (and nonischemic) cardiomyopathy. In this issue of Circulation Research, Small et al present exciting new data showing that the transcriptional coactivator myocardin-related transcription factor (MRTF)-A plays a critical role in promoting the conversion of cardiac fibroblasts to myofibroblasts activating a fibrotic gene program.7 MRTF-A is a member of the MRTF family of transcriptional coactivators, which also includes myocardin and MRTF-B (reviewed elsewhere8). The human MRTF-A gene, which had previously been designated as MAL and MKL-1, is located at chromosome 22q13.2.9 MRTF-A is expressed in multiple cell lineages including undifferentiated embryonic stem cells and fibroblasts.10,11 MRTF-A is a remarkably potent transcriptional coactivator that physically associates with the MADS box transcription factor serum response factor (SRF) to synergistically activate transcription of a subset of CArG box–containing genes.9–11 MRTF-A and -B share multiple conserved domains including an N-terminal RPEL domain that facilitates binding to actin.8,12 Despite overlapping patterns of expression and conserved domains and structure, MRTF-A– and MRTF-B–null mutant mice display distinct phenotypes.13,14 Although there are many possible explanations for this surprising finding, it is most likely attributable to subtle differences in protein structure and/or differences in patterns of expression.10,11 The association of inducible transcriptional coactivators with transcription factors provides an efficient mechanism to expand and modulate information encoded within the genome. Transcriptional coactivators transduce signals regulating genes involved in cellular differentiation, migration, and proliferation. Because MRTF-A is able to transduce both biomechanical and humoral signals, it is particularly well suited to coordinate the response of the heart following an acute MI. MI and cardiac ischemia profoundly alter the biomechanical properties of the heart. As schematically depicted in the Figure, mechanical forces are transduced via Rho GTPases to the cytoskeleton.9 Activation of Rho induces actin polymerization via the Rho kinase (ROCK)/LIM kinase (LIMK)/cofilin pathway, stabilizing F-actin and promoting the assembly of G-actin monomers into F-actin filaments. In response to falling concentrations of G-actin, MRTF-A localThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the University of Pennsylvania Cardiovascular Institute and Department of Medicine, Philadelphia. Correspondence to Michael S. Parmacek, MD, 9123 Founders Pavilion, 3400 Spruce St, Philadelphia, PA 19104. E-mail michael.parmacek@ uphs.upenn.edu (Circ Res. 2010;107:168-170.) © 2010 American Heart Association, Inc.