Noncanonical WNT activation in human right ventricular heart failure

A significant barrier to developing therapies to treat right ventricular (RV) remodeling and RV failure (RVF) has been a lack of understanding for the molecular pathways that are specifically activated in pathologic human RV remodeling. Since murine models have suggested involvement of Wnt signaling in pathologic RV remodeling, we used a candidate gene approach to study differential WNT expression in human RV remodeling using RVs from three groups: nonfailing donors, explanted dilated and ischemic cardiomyopathy with either preserved RV function or with RVF. We identified the noncanonical WNT receptor ROR2 as transcriptionally strongly upregulated in RVF. ROR2 protein expression correlated linearly to mRNA expression and to worse RV performance using pretransplant hemodynamic assessments. High ROR2 expression in RVF also correlated to expression of the WNT5A/ROR2/Ca 2+ responsive protease calpain as well as cleavage of its downstream target FLNA, and FLNA phosphorylation, another marker of activation downstream of ROR2. Here we demonstrate robust reactivation of a fetal WNT gene program, specifically its noncanonical arm, in human RVF characterized by activation of ROR2/calpain mediated cytoskeleton protein cleavage.