Abstract 15252: Protection of Cardiomyocytes from Stress-Induced Cytotoxicity by Neuronal Ca2+-Sensor-1
Dysregulation of Ca2+ homeostasis often induces heart failure. Identifying the molecular targets regulating myocyte survival and Ca2+ signals is therefore important for therapeutic purposes. Neuronal Ca2+-sensor-1 (NCS-1) is a small EF-hand Ca2+-binding protein that is important for neuronal functions. However, its cardiac functions remain unclear. Recently, in a study that used NCS-1-/- mice for the first time, we identified 2 novel roles of NCS-1 as a positive regulator of immature heart contraction and hypertrophy. We observed that neonatal NCS-1-/- mice had high mortality rates; therefore, in the present study, we assessed the hypothesis that NCS-1 plays beneficial roles in cardiac survival, especially under stressed conditions. Cultured neonatal mouse ventricular myocytes (NMVMs) from NCS-1-/- mice were found to be more susceptible than WT NMVMs to several kinds of stressors (e.g., serum/glucose depletion and oxidative stress), which was assessed by the time to cessation of spontaneous beating, LDH release, and live/dead cell staining. Such cytotoxicity was largely prevented by WT NCS-1 overexpression but not by the low Ca2+-binding NCS-1 mutant E120Q, suggesting that NCS-1 protects cardiomyocytes from stress-induced cytotoxicity in a Ca2+-dependent manner. NCS-1-/- hearts were more susceptible than WT hearts to ischemia-reperfusion injury (infarct area, 39% ± 3.5% and 22% ± 4.1% for NCS-1-/- and WT mice, respectively; n = 6 for each). In both NMVMs and whole hearts, a major survival pathway-PI3K/Akt signaling-showed significantly reduced activity in the NCS-1-/- mice. Using the RNAi technique, we identified phosphatidylinositol 4-kinase (PI4K; located upstream of the PI3K/Akt pathway) as an NCS-1 target that promotes cardiac survival; NCS-1 physically interacts with and activates PI4K in native mouse hearts and treatment of WT-NMVMs with miRNAs for PI4K resulted in decreased resistance to stress-induced cytotoxicity, as observed in NCS-1-/- myocytes. In conclusion, NCS-1 acts as a survival-promoting factor in cardiomyocytes under stressed conditions, and this is at least partially mediated via PI4K activation, followed by PI3K/Akt pathway activation.
- © 2012 by American Heart Association, Inc.