Sudden cardiac death due to fatal arrhythmias is responsible for approximately 400,000 deaths annually in the US and is responsible for approximately half of the mortality in patients with congestive heart failure, presumably due to ventricular arrhythmias. In addition, the risk of drug induced arrhythmias is approximately doubled by heart failure. Decrease in the repolarizing potassium channel IKs is seen in human failing hearts and animal models of heart failure but the mechanism for this IKs reduction is largely unknown. Calcium dependent PKC isoforms (cPKC) signaling is strongly activated in heart failure. Here we propose a novel signaling pathway underlying arrhythmogenesis in congestive heart failure. We propose that sustained cPKC activation leads to decrease in IKs via the channel internalization controlled by cPKC-KCNE1(S102) pathway underlying an increase in action potential duration (APD) and calcium overload, setting the stage for progression of heart failure and cardiac arrhythmias. To test our hypothesis we will: 1) determine whether sustained PKC?-activation inhibits IKs membrane expression via KCNE1(S102) phosphorylation in cardiomyocytes leading to APD prolongation, 2) develop KCNE1 and KCNQ1 based peptides that specifically inhibit IKs internalization, 3) determine the contribution of cPKC mediated IKs internalization to QT prolongation and arrhythmia propensity in a heart failure mouse model. By performing the work in this proposal we expect to uncover a major signaling pathway underlying the development of cardiac arrhythmias, in particular for heart failure patients. We expect our work will unveil cPKC inhibitors as a novel class of antiarrhythmic drugs. Because cPKC inhibitors are also thought to affect calcium handling and may have non-cardiac effects, we expect to develop new IKs-target drug prototypes that more specifically inhibit QT prolongation and arrhythmias associated with heart failure.
Sudden cardiac death due to fatal arrhythmias is responsible for approximately 400,000 deaths annually in the US and is a major cause of mortality in patients with congestive heart failure. In addition, the risk of drug induced arrhythmias is approximately doubled by heart failure. Approximately half of the heart failure related deaths are sudden, and presumably are due to ventricular arrhythmias. The studies on this proposal focus on a novel signaling pathway underlying arrhythmogenesis in congestive heart failure and the development of novel antiarrhythmic drugs that specific target ion channel dysfunction that occur in heart failure. By performing the work in this proposal we expect to uncover a major signaling pathway underlying the development of cardiac arrhythmias, in particular for heart failure patients. We expect our work will unveil cPKC inhibitors as a novel class of antiarrhythmic drugs. Because cPKC inhibitors are also thought to affect calcium handling and may have non-cardiac effects, we expect to develop new IKs-target drug prototypes that more specifically inhibit QT prolongation and arrhythmias associated with heart failure.
| Ruwald, Martin H; Xu Parks, Xiaorong; Moss, Arthur J et al. (2016) Stop-codon and C-terminal nonsense mutations are associated with a lower risk of cardiac events in patients with long QT syndrome type 1. Heart Rhythm 13:122-31 |
| O-Uchi, Jin; Sorenson, Jaime; Jhun, Bong Sook et al. (2015) Isoform-specific dynamic translocation of PKC by ?1-adrenoceptor stimulation in live cells. Biochem Biophys Res Commun 465:464-70 |
| O-Uchi, Jin; Rice, J Jeremy; Ruwald, Martin H et al. (2015) Impaired IKs channel activation by Ca(2+)-dependent PKC shows correlation with emotion/arousal-triggered events in LQT1. J Mol Cell Cardiol 79:203-11 |
