Abstract 15453: CaMKII Plays a Critical Role in Pressure Overload-Induced Left Ventricular Hypertrophy by Modulating Foxp1 Expression
Introduction: The necessity of IL-6 signaling in pressure overload-induced left ventricular hypertrophy remains controversial. Whether Calcium/calmodulin-dependent kinase II (CaMKII) participates in IL-6-induced and pressure overload-induced hypertrophic signaling remains unknown.
Hypothesis: CaMKII acts as a nodal point for integrating IL-6 signaling in pressure overload induced hypertrophic molecular pathways.
Methods and Results: In vitro, exposure to IL-6 for 24 h induced hypertrophy in H9c2 cells. This hypertrophic response was associated with robust increase in phospho-CaMKII levels in IL-6-treated cells, and accompanied by increase in myocyte hypertrophy markers. Interestingly, Mef2a levels also increased, and this was associated with reduced Foxp1 expression, which has Mef2a specific binding site at CTAAAAATAG (-401 ~ -391) in Foxp1 promoter sequence. These effects were inhibited by selective CaMKII inhibitor KN-62. Next, we performed transverse aortic constriction (TAC) in IL-6-/- mice and wild-type (WT) C57BL/6J mice to induce hypertrophy. After 6 wks, TAC-induced hypertrophy was significantly attenuated in IL-6-/- mice compared with WT mice, documented by necropsy findings, echocardiography, and LV morphometry. Phospho-CaMKII levels increased significantly in control mouse hearts at 2 wks after TAC, while this increase was significantly blunted in IL-6-/- hearts (Figure). Moreover, and consistent with attenuated CaMKII activity, the expression of Mef2a was lower and expression of Foxp1 was higher in IL-6-/- hearts after TAC compared with controls.
Conclusions: We identify a novel signaling module whereby regulation of Foxp1 by CaMKII plays a critical role in pressure overload-induced and IL-6-mediated cardiac hypertrophy. These molecular insights may lead to formulation of novel therapeutic agents for LV hypertrophy and dysfunction.
Author Disclosures: L. Zhao: None. G. Cheng: None. R. Jin: None. L. Chen: None. A. Samanta: None. M. Girgis: None. H.K. Elias: None. A. Davani: None. K. Choksi: None. R. Vincent: None. Y. Yang: None. J. Hauptman: None. B. Dawn: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.