Abstract 15923: CaMKII Links ER Stress Signaling in Pressure Overload-Induced Left Ventricular Hypertrophy and Failure
Introduction: Recent evidence indicates that the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a key role in pathogenesis of cardiac hypertrophy and failure. The cytosolic calcium resulting from endoplasmic reticulum (ER) also involves CaMKII. However, the molecular connection between ER stress and LV hypertrophy remains unclear.
Hypothesis: We hypothesized that CaMKII serves as the molecular link between ER stress and LV hypertrophy.
Methods: We used mice with genetic deletion of C/EBP Homologous Protein (CHOP), a mediator of ER stress. Transverse aortic constriction (TAC) or sham surgeries were performed in age-matched male CHOP knockout (KO) mice and controls to induce pressure overload. Serial echocardiography was performed prior to (baseline, BSL) and weekly after TAC. Mice were sacrificed after 6 weeks for measurement of heart weight, morphometry, histology, and protein assays. Separate groups of CHOP KO and control mice were sacrificed at 2 weeks after TAC for protein assays.
Results: Pressure overload resulted in progressive LV dysfunction (Figure) and hypertrophy in control mice compared with baseline. At 6 wks after TAC these adverse effects of pressure overload were significantly attenuated in CHOP KO mice as evidenced by greater LV EF (Figure) and smaller LV mass compared with controls. Compared with control hearts, phosphorylation of CaMKII was significantly reduced in CHOP KO hearts at 2 and 6 weeks after TAC (Figure). The phosphorylation of eIF2α, a signaling molecule upstream of CHOP in the ER stress pathway was significantly increased in CHOP KO hearts after TAC compared with control mice (Figure).
Conclusion: Genetic deletion of CHOP attenuates LV hypertrophy and dysfunction induced by pressure overload; and CaMKII serves as a link between ER stress and hypertrophic signaling. Potential modulation of CaMKII and CHOP signaling may be used to ameliorate LV hypertrophy in patients with cardiovascular diseases.
Author Disclosures: G. Cheng: None. L. Zhao: None. L. Chen: None. X. Chen: None. A. Davani: None. A. Samanta: None. M. Girgis: None. H. Elias: None. Y. Yang: None. R.J. Vincent: None. J. Hauptman: None. B. Dawn: None.
- © 2014 by American Heart Association, Inc.