The ER Unfolded Protein Response Effector, ATF6, Reduces Cardiac Fibrosis and Decreases Activation of Cardiac Fibroblasts

Activating transcription factor-6 alpha (ATF6) is one of the three main sensors and effectors of the endoplasmic reticulum (ER) stress response and, as such, it is critical for protecting the heart and other tissues from a variety of environmental insults and disease states. In the heart, ATF6 has been shown to protect cardiac myocytes. However, its roles in other cell types in the heart are unknown. Here we show that ATF6 decreases the activation of cardiac fibroblasts in response to the cytokine, transforming growth factor beta (TGF beta), which can induce fibroblast trans-differentiation into a myofibroblast phenotype through signaling via the TGF beta-Smad pathway. ATF6 activation suppressed fibroblast contraction and the induction of alpha smooth muscle actin (alpha SMA). Conversely, fibroblasts were hyperactivated when ATF6 was silenced or deleted. ATF6 thus represents a novel inhibitor of the TGF beta-Smad axis of cardiac fibroblast activation.