The KChIP2-JNK2 axis as a therapeutic target for sudden cardiac death

Project Summary Half of heart failure (HF) patients die suddenly, termed as sudden cardiac death (SCD), while HF affects over 5 million people in the United State alone. The current ACC/HF/AHA guidelines recommend implantable cardioverter-defibrillator (ICD) therapy for the secondary prevention of SCD and primary prevention in HF patients. However, significant mortality benefits in ICD implanted HF patients was not shown in randomized clinical trials. Therefore, development of effective therapies is urgently needed. HF myocardium exhibits electrophysiologic pathological remodeling that underlies the development of non-reentrant mechanisms (triggered activity) as well as slowing of conduction in nonischemic HF human hearts that underlie development of reentry. Sarcoplasmic reticulum (SR) Ca2+ mishandling impairs excitation-contraction coupling, to play a key role in triggered arrhythmia in HF. Our group recently discovered a previously unknown form of kinase-on-kinase crosstalk where JNK2 enhances CaMKII gene expression and activity, CaMKII-regulated SR Ca mishandling (leak/overload), arrhythmic Ca activities, and triggered delayed afterdepolarization (DADs) in the heart. We further demonstrated a JNK2-specific action (independent of CaMKII) in SR Ca overload via enhanced SERCA2 Ca uptake, which exacerbates the JNK2-CaMKII-evoked diastolic SR Ca leak and arrhythmogenesis. In addition, we found that JNK2 downregulates gap junction Cx43 gene expression and impairs cell-to-cell communication, which promotes reentrant substrate to sustain triggered activities. Our pilot studies show that JNK2 is markedly activated and upregulated in explanted failing left ventricles (LV) from dilated cardiomyopathy (DCM) patients compared to healthy control hearts suggesting that JNK2 could be an unexplored contributor to SCD in HF. Although our preliminary data suggest a key implication for JNK2 in the mechanisms leading to SCD, the upstream pathway leading to this upregulation of JNK2 remains unknown. Importantly, downregulation of the Potassium Channel Interacting Protein, KChIP2, has been linked to arrhythmias and SCD. In the absence of KChIP2 there is enhanced susceptibility to ventricular arrhythmias, while restoring KChIP2 expression in a rodent model of hypertrophy delayed the progression to HF and reduced arrhythmias. Importantly, we demonstrated that KChIP2 is found in the nucleus where it can act as a transcriptional repressor suggesting it could contribute to arrhythmia mechanisms through transcriptional regulation of cardiac genes. Our preliminary data suggest that KChIP2 can bind and repress the expression of JNK2. Thus, our central hypothesis for this proposal is that the KChIP2-JNK2 axis plays a critical role in mechanisms leading to arrhythmias and SCD. This proposal will aim on answering two important questions: 1) how does KChIP2 regulate JNK2 expression? 2) how does the KChIP2-JNK2 axis promote SCD in HF? Importantly, we will test therapeutic interventions of overexpression of KChIP2 and/or inhibition of JNK2 as novel anti-arrhythmia strategies for HF patients.