Abstract 21468: A Novel CaMKII/ERK Interaction n the Heart Sustains Cardiac Hypertrophy in Spontaneously Hypertensive Rats
The molecular mechanism underlying Cardiac hypertrophy involves, among others, abnormal intracellular Ca++ dynamics. Ca++/Calmodulin protein kinase II (CaMKII) activation mediates Ca++ signaling in the hypertrophic transduction pathways. Nevertheless, the mechanism by which CaMKII integrates with other pathways is incompletely understood. We showed that phenylephrine (PE) induces cell proliferation through CaMKII and ERK complex formation, promoting phosphorylation and nuclear localization of both proteins. We hypothesize that the association with ERK, promotes nuclear localization in hypertrophic cardiomyocytes. In H9C2 cardiomyoblasts, PE induces both ERK and CaMKII activation and interaction which can both be reduced by the non selective CaMKs inhibitor KN93, by the selective CaMKII inhibitor AntCaNtide, and by the MEK/ERK inhibitor UO126. Next, we found that PE induces a time-dependent accumulation of both ERK and CaMKII into the nucleus, prevented by AnTCaNtide and UO126 pretreatment, supporting the hypothesis that ERK activation is required for CaMKII nuclear localization. In order to determine the role of CaMKII in vivo cardiac hypertrophy, Spontaneously Hypertensive Rats (SHR) were subjected to intracardiac injection of AnTCaNtide (ANTS, 50μg/kg, n=8). Sham groups of SHR (SS, n=8) and normotensive rats (WKY, n=7) were subjected to intracardiac injection of saline. After 3 from the treatment, we performed an ultrasound (VeVo-Visualsonic) cardiac evaluation and an invasive (Millar) arterial blood pressure (BP) measurement in the rats. Mean arterial pressure and body weight were similar between SS and ANTS, but we observed in ANTS a significant reduction of both cardiac size (ANTS vs SS: Heart weight/body ratio 3.961±0.02586 vs 4.177±0.02583, p<0.05 ) and thickness of interventricular septum (ANTS vs SS: 1.821±0.01063 vs 1.918±0.01797, p<0.05). In ANTS hearts, by western blot, we observed a significant reduction of CaMKII and ERK phosphorylation levels. In conclusion, a crosstalk between CaMKII and ERK sustain the activation of both kinases both in vitro and in vivo. This CaMKII-ERK interaction offers a novel therapeutic approach to limit pathological cardiac hypertrophy.
- © 2010 by American Heart Association, Inc.