Ror2-mediated Proteostatic Disruption As A Novel Mechanism For Right Ventricular Failure

No therapies exist to reverse right ventricular failure (RVF), in part because RVF molecular drivers have been incompletely characterized. We recently identified RVF-severity dependent re-expression of the developmental noncanonical WNT receptor Ror2 in dilated and ischemic cardiomyopathy RV. We now demonstrate that Ror2 plays a novel role in regulating cardiomyocyte proteostasis (Figure). NRVMs with Ror2 overexpression (Ror2 OE ) are smaller, rounder and demonstrate fragmented sarcomeres, loss of intercalated disc proteins, and reduced ubiquitination. Knockdown of Ror2 (Ror2 KD ) reveals opposing phenotypes. RNAseq of Ror2 OE vs Ror2 KD revealed striking downregulation of chaperone genes (Hspa1a/b, Cryab, Hsp90aa1, Hsph1/d1, etc.) and upregulation of genes involved in proteolysis (Rcn3, Nkd2, Mapk12). Using Suc-LLVY-AMC and GFP-degron, we find that proteasome activity is enhanced in Ror2 OE and inhibited in Ror2 KD . MG-132 proteasomal inhibition reversed structural phenotypes in Ror2 OE NRVMs. In vivo cardiac Ror2 OE caused RV dilation and systolic and diastolic dysfunction, more prominently in male mice. In male Ror2 OE RVs, proteasome activity was enhanced and ubiquitin staining of RV cardiomyocytes was reduced. Finally, PAB caused a 5-fold increase in triton soluble and 40-fold increase in triton insoluble Ror2 expression, which correlated to severity of RV hypertrophy and dilation. Studies to test the efficacy of Ror2 KD for PAB RVF are ongoing. In sum, our work suggests that reactivation on non-canonical Wnt signaling contributes to RVF, unveiling a novel potential therapeutic target.