Abstract 260: The ER Unfolded Protein Response Effector, ATF6, Reduces Fibrosis and Moderates Activation of Cardiac Fibroblasts

Fibroblasts in the heart respond to myocardial injury by infiltrating the affected area and differentiating into new cell types called myofibroblasts. These cells are characterized both by the induction of contractile proteins and the secretion of extracellular matrix proteins which form fibrotic scar tissue. Investigating the factors governing fibroblast activation is key to understanding how these cells function in the heart and may be key to future therapeutic strategies. Activating transcription factor 6 (ATF6), an effector of the endoplasmic reticulum unfolded protein response, plays critical roles in development, as well as in the differentiation of certain cell types, though it has not been studied in this regard in the heart. Our lab has demonstrated that ATF6 in cardiac myocytes is cardioprotective in vivo during heart disease. However, ATF6 has not been studied in cardiac fibroblasts and its effect on fibrosis in the heart is unknown. We hypothesized that ATF6 in fibroblasts is an important regulator of their function. Fibroblast activation markers including αSMA were increased in infarcted hearts with global ATF6 deletion. Additionally, hearts with pressure overload showed increased fibrosis staining in global ATF6-null mice relative to WT hearts. In isolated adult murine ventricular fibroblasts (AMVF), loss of ATF6 induced myofibroblast markers with and without the activation stimulus TGFβ. ATF6 loss of function also enhanced the effect of TGFβ on fibroblast contraction. These effects were associated with an increase in Smad phosphorylation, a crucial step in the TGFβ pathway. Interestingly, the effect of ATF6 loss of function in AMVF was erased when treated with a TGFβ receptor inhibitor. Additionally, when ATF6 was overexpressed or when endogenous ATF6 was chemically activated, myofibroblast markers were reduced and activation by TGFβ was blunted. ATF6 activation was associated with induction of several TGFβ/Smad pathway negative regulators including SMURF1, SMURF2, and PMEPA1, though none of these are known to be ATF6 target genes. These data suggest that ATF6 plays an important role in moderating fibroblast activation and this may contribute to previously reported roles for ATF6 in preserving cardiac function post-injury.