Year: 2026
Type: article
Abstract: Background: No therapies exist to reverse right ventricular failure (RVF), and the molecular mechanisms that drive RVF remain poorly studied. We recently reported that the developmentally restricted noncanonical WNT receptor ROR2 is upregulated in human RVF in proportion to severity of disease. Here we test mechanistic role of ROR2 in RVF pathogenesis. Methods: ROR2 was overexpressed or knocked down in neonatal rat ventricular myocytes (NRVMs). ROR2-modified NRVMs were characterized using confocal microscopy, RNAseq, proteomics, proteostatic functional assays, and contractile properties with pacing. The impact of cardiac ROR2 expression was evaluated in mice by AAV9-mediated overexpression and by AAV9-mediated delivery of shRNA to knockdown ROR2 in a pulmonary artery banded pressure overload RVF model. ROR2-modified mice were evaluated by echocardiography, RV protein synthetic rates and proteasome activity. Results: In NRVMs, 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 (UPS) with dramatic impacts on sarcomere and cytoskeletal structure and function. In mice, forced cardiac ROR2 expression is sufficient to disrupt proteostasis and drive RVF, while conversely ROR2 knockdown partially rescues proteostasis and cardiac function in a pressure overload model of RVF. Conclusions: In sum, ROR2 is a key driver of RVF pathogenesis through proteostatic disruption and, thus, provides a promising target to treat RVF.
Source: Circulation
Authors: Hali Hartman, Genevieve Uy, Keita Uchida, Emily A. Scarborough, Yifan Yang, Eric 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 Prosser, Zoltan Arany, Jonathan J. Edwards
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Mechanisms of Improved Diastolic Function in Human Heart, Dynamics of RNA regulation and noncanonical translation between cell states, Endogenous Cardiac Repair in Humans, Integrative genomics of human heart failure, Detyrosinated microtubules in cardiomyocyte mechanics, Mechanical Stress-Dependent Remodeling of the Cardiac Microtubule Network, Defining the Role of ROR2 in Right Ventricular Failure Pathogenesis, Branched chain amino acids in heart failure, Training Program in Cardiovascular Biology and Medicine
OpenAlex ID: W4407072942