Abstract Tu068: Calmodulin Kinase II is a Mutation-Specific Driver of Disease in Hypertrophic Cardiomyopathy

• DOI: 10.1161/res.135.suppl_1.tu068
• Publication Date: 2024-10-09T14:03:28Z
• Authors: Garrett Hauck; Catherine Vasquez; Melissa Lynn; Matthew Klass; Paul Langlais; Shanna Hamilton; Jil Tardiff

In the heart, Ca/Calmodulin Kinase IIδ (CaMKIIδ) functions to maintain electromechanical and calcium homeostasis. Post-translational modifications (PTMs) of CaMKIIδ render its activity autonomous Ca/CaM. hypertrophic cardiomyopathy (HCM), increased levels are linked disease progression. We have shown that pathogenic role in HCM is mutation-specific: elevated cardiac troponin T (cTnT)-R92W mice, but not cTnT-R92L mice. These results pose a clinically relevant critical question: what trigger for dysregulation HCM, such it only found with certain mutations? hypothesize from distinct thin filament (TF) biophysical properties altered by point mutations. cTnT-R92W TFs display faster dissociation kinetics compared wild type TFs, whereas slower kinetics, thus we propose accelerated as mutation-specific dysregulation. To test this, will use mass spectrometry following immunoprecipitation assess phosphorylation at Thr-287 oxidation Met-281/282 mice expressing R94H, I79N, or R92W mutations cTnT, which exhibit differing kinetics. Preliminary data shows PTMs can be readily detected. also biosensor CaMKAR cardiomyocytes isolated these evaluate activity. genetic inhibition improves diastolic function atrial remodeling. aim efficacy small molecule inhibitor ruxolitinib (rux) Two-week treatment rux systolic function, has no effect nontransgenic controls, implicating potential therapeutic option HCM. continue studies, explore changes handling three mouse models further establish mechanistic pathways extend longer timepoints an therapeutic.