ROR2 Drives Right Ventricular Heart Failure Through Disruption of Proteostasis.

Forced cardiac overexpression of ROR2 in mice disrupts proteostasis and drives right ventricular failure in a pressure-overload RVF model.

• Why it matters: Right ventricular failure has no therapies that reverse it, and the molecular mechanisms driving RVF are understudied despite ROR2 being upregulated with disease severity.
• What they did: Neonatal rat ventricular myocytes were engineered to overexpress or knock down ROR2, then assessed with confocal microscopy, RNA sequencing, proteomics, proteostatic functional assays, and pacing; mice received AAV9 ROR2 overexpression or shRNA knockdown in pulmonary artery banding.
• The result: ROR2 dysregulated translation–folding coordination, increasing ubiquitin proteasome–mediated clearance and impairing sarcomere/cytoskeletal structure and function; proteasome inhibition or chaperone restoration partially rescued deficits, while Ror2 knockdown partially rescued proteostasis and right-ventricle structure and function.