October 26, 2026Circulation
ROR2 Drives Right Ventricular Heart Failure Through Disruption of Proteostasis
Hali HartmanGenevieve UyKeita UchidaEmily A. ScarboroughYifan YangEric W. BarrSpencer WilliamsRyan T. SantilliSanam L. KavariJeff BrandimartoLi LiLing LaiJoanna GriffinNora YucelSwapnil ShewaleHari RajagopalDeborah EatonTanis J. DorwartKenneth B. MarguliesCrystal S. ConnKenneth B. MarguliesBenjamin L. ProsserZoltàn AranyJonathan J. Edwards
Key result
ROR2 knockdown partially rescues right ventricular structure and function by restoring proteostasis in pressure overload.
Why the study?
No therapies exist to reverse right ventricular failure (RVF), and its underlying molecular mechanisms remain understudied. Although ROR2 is upregulated in human RVF in proportion to disease severity, its mechanistic role in RVF pathogenesis was untested.
Does ROR2 knockdown rescue proteostasis and improve right ventricular structure and function in preclinical models of right ventricular failure?
Key Points
- To determine the mechanistic role of the noncanonical WNT receptor ROR2 in driving right ventricular heart failure pathogenesis.
- Overexpressed and knocked down ROR2 in neonatal rat ventricular myocytes to evaluate effects via confocal microscopy, RNA sequencing, proteomics, proteostatic functional assays, and pacing contractility tests.
- Assessed cardiac ROR2 via AAV9-mediated overexpression and AAV9-mediated shRNA knockdown in mice subjected to pulmonary artery banding-induced pressure overload, measuring outcomes by echocardiography, histology, and proteasome capacity assays.
- ROR2 uncoupled protein translation and folding in cardiomyocytes, leading to excess degradation by the ubiquitin-proteasome system and damage to sarcomeric and cytoskeletal structure and function.
- Ubiquitin-proteasome system inhibition or chaperone restoration partially rescued structural and contractile impairments induced by ROR2 in vitro.
- Cardiac ROR2 overexpression drove right ventricular failure in mice, while Ror2 knockdown preserved proteostasis and partially restored right ventricular structure and function during pressure overload.
Structured PICO
Does ROR2 knockdown rescue proteostasis and improve right ventricular structure and function in preclinical models of right ventricular failure?
P
Population
Preclinical study in neonatal rat ventricular myocytes and mice with pulmonary artery banding-induced right ventricular failure evaluating ROR2 overexpression and knockdown.
I
Intervention
ROR2 overexpression or knockdown in neonatal rat ventricular myocytes (plus ubiquitin proteasome system inhibition or chaperone expression restoration); AAV9-mediated ROR2 overexpression or AAV9-mediated delivery of short hairpin RNA to knockdown ROR2 in mice
O
Outcome
Proteostasis (coordination between protein translation and folding, ubiquitin proteasome system clearance, right ventricle protein synthesis and proteasome capacity) and right ventricular structure and function (assessed by confocal microscopy, pacing for contractile properties, echocardiography, and histology)surrogate
Preclinical evidence demonstrates that ROR2 drives right ventricular failure by disrupting cardiomyocyte proteostasis, identifying ROR2 inhibition as a potential therapeutic target for right ventricular failure.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“When I was a postdoctoral fellow, I identified ROR2, a cell surface receptor, as a candidate target for right ventricular failure. Our preliminary work revealed a previously unknown role for ROR2 in affecting how cardiomyocytes balance protein production and turnover, a process termed “proteostasis”.”
Implication
ROR2 inhibition may represent a target in right ventricular failure; hypothesis-generating in animal models and leaves open clinical translation.
Abstract
BACKGROUND: 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 ROR2 (receptor tyrosine kinase-like orphan receptor 2) is upregulated in human RVF in proportion to severity of disease. Here we test the mechanistic role of ROR2 in RVF pathogenesis. 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 ROR2 in a pulmonary artery banded pressure overload model of RVF. ROR2 -modified mice were evaluated by echocardiography, histology, and right ventricle protein synthesis and proteasome capacity. 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 Ror2 knockdown partially rescues proteostasis and right ventricle structure and 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.
Discussion
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Cite This Study
Hartman et al. (2026) studied Right ventricular failure (RVF). AAV9-mediated ROR2 overexpression or shRNA knockdown vs. Control / pressure overload model without ROR2 modification was evaluated on Proteostasis, right ventricular structure, and contractile function. AAV9-mediated ROR2 overexpression in mice disrupted proteostasis to drive right ventricular failure, whereas ROR2 knockdown partially rescued RV structure and function in pressure overload.