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Published on: November 7, 2017
Peroxiredoxin-6 protects against oxidative stress-mediated hypertrophic remodeling in JPH2-A399S knock-in mice
Callum J Quinn1,2, Satadru K Lahiri1,2, Ann P Quick1,2
1Cardiovascular Research Institute, USA.
Background:
Most mutations causing hypertrophic cardiomyopathy (HCM) affect sarcomeric proteins. Mutations in junctophilin-2 (JPH2) are also implicated, but the underlying mechanisms remain unclear. An A405S variant in JPH2 was identified in a male adolescent patient with interventricular septal (IVS) hypertrophy. The corresponding mouse variant (A399S) produces comparable IVS hypertrophy, establishing causality. Prior data indicated that altered intracellular Ca2+ handling is unlikely to be the primary driver.
Methods:
We generated a CRISPR knock-in mouse model carrying the JPH2-A399S variant. Co-immunoprecipitation mass spectrometry and STED nanoscopy were used to identify JPH2 binding partners. Reactive oxygen species (ROS) were assessed with dihydroethidium in isolated myocytes. Adeno-associated virus serotype 9 (AAV9) was employed to overexpress peroxiredoxin 6 (PRDX6) in mutant hearts.
Results:
PRDX6 was identified as a novel and abundant JPH2-interacting protein. PRDX6 expression was selectively downregulated in the IVS of JPH2-A399S mice and was also reduced in human failing hearts. JPH2-A399S mice exhibited increased ROS levels specifically in IVS myocytes. AAV9-mediated PRDX6 overexpression reversed the IVS hypertrophy phenotype.
Conclusions:
These findings identify PRDX6 downregulation and consequent oxidative stress as a key mechanism driving JPH2-A399S-associated HCM. The results reveal a previously unrecognized role for JPH2 in cardiometabolic regulation and suggest that restoring PRDX6 levels may represent a therapeutic strategy for this form of HCM.
