ROR2 Drives Right Ventricular Heart Failure Through Disruption of Proteostasis
Hali Hartman, Genevieve Uy, Keita Uchida, Emily A. Scarborough, Yifan Yang, Eric W. Barr, Spencer Williams, Ryan T. Santilli, Sanam L. Kavari, Jeff Brandimarto, Li Li, Ling Lai, Joanna Griffin, Nora Yucel, Swapnil Shewale, Hari Rajagopal, Deborah M. Eaton, Tanis Dorwart, Kenneth C. Bedi, Crystal S. Conn, Kenneth B. Margulies, Benjamin L. Prosser, Zoltan Arany, Jonathan J. EdwardsBACKGROUND:
No therapies exist to reverse right ventricular failure (RVF), and the molecular mechanisms that drive RVF remain understudied. We recently reported that the developmentally restricted noncanonical WNT receptor
METHODS:
ROR2 was overexpressed or knocked down in neonatal rat ventricular myocytes and then characterized using confocal microscopy, RNA sequencing, proteomics, proteostatic functional assays, and pacing to assess contractile properties. The impact of cardiac ROR2 expression was evaluated in mice by AAV9-mediated overexpression and by AAV9-mediated delivery of short hairpin RNA to knockdown
RESULTS:
In neonatal rat ventricular myocytes, we find that ROR2 profoundly dysregulates the coordination between protein translation and folding. This imbalance leads to excess protein clearance by the ubiquitin proteasome system with dramatic impacts on sarcomere and cytoskeletal structure and function. Inhibiting the ubiquitin proteasome system or restoring chaperone expression is sufficient to partially rescue ROR2-induced structural and contractile deficits in cardiomyocytes. In mice, forced cardiac ROR2 expression is sufficient to disrupt proteostasis and drive RVF, whereas conversely
CONCLUSIONS:
In sum, ROR2 is a key driver of RVF pathogenesis through proteostatic disruption and thus provides a promising target to treat RVF.