3 Key Takeaways
Plain English Summary- 01Core Finding
Here we test the mechanistic role of ROR2 in RVF pathogenesis.
- 02Study Evidence
Tested in a in vivo animal model (preclinical discovery) at the preclinical stage.
- 03Practical Meaning
Early laboratory or animal model findings — human trials are still needed to confirm safety and benefit.
What This Means for You
In sum, ROR2 is a key driver of RVF pathogenesis through proteostatic disruption and thus provides a promising target to treat RVF.
Published in Circulation, these peer-reviewed cardiology findings provide quantitative clinical evidence to inform risk stratification, therapeutic decision-making, and follow-up validation.
The Discovery
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. 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. 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.
How It Works, Simply
This cardiology research focuses on receptor targeting. Researchers evaluated it using an in vivo animal model (Preclinical discovery) at the preclinical stage of medical research.
3 Key Takeaways
Clinical Takeaways- 01Core Finding
Here we test the mechanistic role of ROR2 in RVF pathogenesis.
- 02Study Evidence
Tested in a in vivo animal model (preclinical discovery) at the preclinical stage.
- 03Practical Meaning
Early laboratory or animal model findings — human trials are still needed to confirm safety and benefit.
Biological Mechanism & Study Design
Study Design & Cohort
Animal models
In vivo animal model (Preclinical discovery) · Preclinical
Biological Pathway & Modality
Receptor targeting
Intervention: ROR2 Drives Right Ventricular Heart Failure Through Disruption of Proteostasis
Experimental Findings & Endpoints
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.
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. 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.
Clinical Translation & Practice Context
In sum, ROR2 is a key driver of RVF pathogenesis through proteostatic disruption and thus provides a promising target to treat RVF.
Published in Circulation, these peer-reviewed cardiology findings provide quantitative clinical evidence to inform risk stratification, therapeutic decision-making, and follow-up validation.
The Bottom Line · Clinical Pearl
“In sum, ROR2 is a key driver of RVF pathogenesis through proteostatic disruption and thus provides a promising target to treat RVF.”
Published in Circulation · Current Stage: Preclinical
