Excessive activation of calcium and calmodulin (CaM)-dependent protein kinase II (CaMKII) leads to heart failure and arrhythmias in animal models of cardiac disease and increased CaMKII activity has been found in humans with heart failure and arrhythmias. Most of the CaMKII research to date has been focused on pathways that promote excessive CaMKII activation, however, very little is known about cellular pathways that protect against persistent and excessive CaMKII activation. Our laboratory discovered that oxidation of CaMKII prevents CaM trapping, a phenomenon that leads to excessively prolonged CaMKII activation, but the mechanism for oxidation and its effects on the cardiovascular system are unknown. We identified the site in the main CaMKII isoform in the heart as a novel oxidation target for MICAL1(Molecules Interacting with CasL), one of the 3 known MICAL isoforms. MICALs' only previously known target is actin, and the function of MICALs in the cardiovascular system is unknown. We plan to use various molecular and biochemical techniques to: 1) measure oxidation of CaMKII by each of the 3 MICAL isoforms and quantify CaM trapping 2) measure the effects of MICAL oxidation resistant and MICAL oxidation mimetic CaMKII mutants on CaM trapping. These studies are designed to test a novel and unanticipated MICAL-dependent pathway for preventing excessive CaMKII activity. We plan to use these studies as a platform to ultimately study this novel pathway in cardiac physiology and disease using genetically engineered mice.
Cardiovascular disease continues to be the number one cause of death in the USA and worldwide. Excessive activation of calcium and calmodulin (CaM)-dependent protein kinase II (CaMKII) leads to heart failure and arrhythmias in animal models of cardiac disease and increased CaMKII activity has been found in humans with heart failure and arrhythmias. Cellular pathways that protect against persistent and excessive CaMKII activation may become an important target for preventing heart failure and arrhythmias.
