Abstract 19641: Kv 4.3 Expression Improves Cardiac Function in Heart Failure Mice

Abstract

Background: It is known that CaMKII inhibition improves contractility in failing ventricle. However, we reported that drug and genetic CaMKII inhibition deteriorates diastolic function. We recently uncovered a mechanism that I to channel Kv 4.3 inhibits CaMKII activation by directly binding to the CaM binding sites. Unfortunately, this endogenous CaMKII inhibitor is down-regulated in heart failure (HF). Objective: We have tested whether Kv4.3 expression in HF ventricular myocytes can improve contractility without impairment of diastolic function. Methods: HF was induced in mice by severe aortic thoracic banding (sTAB). Kv4.3 was transfected in HF mouse left ventricle (LV) by myocardium Ad-Kv4.3 injection in the week two after sTAB. Heart function was assessed by echocardiography at the day before (day 0) and day 7 after adenovirus injection, respectively, while sarcoplasmic reticulum (SR) Ca 2+ leak, Ca 2+ transient and sarcomere shortening and relaxation were recorded in HF ventricular myocytes with Kv4.3 transfection. Results: HF was produced in one week after sTAB and heart function then remains stable from the post-sTAB week 2 to 5. Compared to the HF mice transfected with Ad-β-gal (control), LV myocytes transfected with Ad-Kv 4.3 showed a reduction of overall CaMKII activity by 10 ± 0.5 % with a reduction of CaMKII-dependent phosphorylation of PLB-Thr17 (13 ± 1.3 %) and RyR-2815 (10 ± 1.2 %), indicating only the localized CaMKII inhibition in the SR microdomain, consistent with the membrane distribution of Kv4.3. Kv4.3 transfection in HF mice produced a significant increase in systolic function (increased EF) and improvement of diastolic function (reduced E/E’). LV myocytes transfected with Kv4.3 showed a significant reduction of SR Ca 2+ leak, an increase in Ca 2+ transient and sarcomere shortening. Importantly, unlike drug inhibition, Kv4.3 transfected HF myocytes showed unchanged sarcomere relaxation, FDAR, and myofilament sensitivity to Ca 2+ . This is associated with an unchanged CaMKII-dependent troponin-I phosphorylation. Conclusion: Our results suggest that Kv4.3 expression (restoration) in failing ventricle can improve contractility without deterioration of relaxation, likely via inhibition of the compartmentalized CaMKII.