Abstract 81: Beta-catenin Loss-of-function in Cardiac Fibroblasts Attenuate Cardiac Fibrosis After Transverse Aortic Constriction in Mice

Abstract

Background: Cardiac fibrosis increases myocardium stiffness, impairs cardiac function and contributes to heart failure. Activated fibroblasts produce excessive extracellular matrix leading to fibrosis and impaired cardiac function. Pathologically activated canonical Wnt signaling has been implicated in the pulmonary-, renal-, dermal- and liver fibrosis as well as in scarring after myocardial infarction. We hypothesize that Wnt/β-catenin signaling contributes to cardiac fibroblast (CF) activation and β-catenin loss-of-function (βLOF) in CFs reduces fibrosis and preserves cardiac function. Methods and Results: The role of Wnt/β-catenin signaling in CF activation was studied using in vitro CF culture and in vivo genetic manipulation. Postnatal (P)0, P8 and P60 CFs were isolated and cultured. Wnt1 treatment significantly activated CFs, while Wnt inhibition (XAV) completely blocked Wnt1-induced CF activation as determined by αSMA staining. Interestingly, XAV also partially abrogated CF activation induced by TGFβ. In vivo, PeriostinMerCreMer (Pn) or Tcf21MerCreMer (T21) mice were crossbred with βLOF and ROSAmTmG. At baseline, CFs were labeled by T21 but minimal activity was observed with Pn. Accumulation of CFs labeled by Pn or T21 Cres was observed in myocardium 8 weeks after TAC. Inducible CF-specific βLOF transgenic mice (Pn-βLOF or T21-βLOF) were subjected to transverse aortic constriction (TAC) or sham surgeries. βLOF was induced post-surgery via tamoxifen. In sham-operated mice, no difference in cardiac function or morphology was observed between βLOF and control mice. In mice subjected to TAC, cardiac function, as measured by echocardiography, was significantly improved, and the interstitial and peri-vascular fibrosis, as well as heart weight to tibia length ratios, were significantly reduced in the βLOF group, compared to controls, 8 weeks after TAC. Thus, induction of βLOF in CFs after TAC leads to improved cardiac performance, decreased fibrosis, and reduced maladaptive cardiac remodeling. Conclusions: βLOF in CFs inhibits myo-fibroblast activation, reduces cardiac fibrosis and preserves cardiac function in TAC induced cardiac injury.