Abstract 17333: CHOP Serves as a Positive Feedback Toward Activation of CaMKII in ER Stress Mediated-apoptosis and Cardiac Dysfunction: Novel Signaling Pathway in Cardiac Pressure Overload
Introduction: Increased apoptosis accompanies the transition from compensated left ventricular (LV) hypertrophy to failure. CCAAT-enhance-binding protein homologous protein (CHOP) is a key molecule in ER stress-mediated apoptosis. Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a pivotal role in LV hypertrophy and dysfunction. The interplay between CHOP and CaMKII remains unknown.
Hypothesis: CHOP signaling is essential for CaMKII activation in ER stress-mediated apoptosis and LV dysfunction induced by pressure overload.
Methods: Transverse aortic constriction (TAC) was performed in CHOP knockout (CHOP-/-) and wild-type (WT) mice. Cardiac structure and function were assessed by serial echocardiography prior to and until 6 weeks after TAC. In vitro, ER stress was induced by thapsigargin (TG) in H9c2 cells and adult cardiomyocytes from WT and CHOP-/- mice.
Results: Pressure overload induced progressive LV hypertrophy and dysfunction in WT control mice compared with baseline. At 6 wks after TAC these adverse effects of pressure overload were significantly attenuated in CHOP-/- mice as evidenced by greater LV EF (Figure) and reduced cardiomyocyte apoptosis rate compared with controls. In vitro, TG activated ER stress signaling pathway with increased expression of phospho-CaMKII in early phase and CHOP in late phase. The increase in p-CaMKII was blunted in CHOP-/- cardiomyocytes. These data suggest that CHOP serves a positive feedback toward activation of CaMKII in late phase of ER stress followed by corresponding changes in apoptotic cells confirmed by studies both in vitro and in vivo.
Conclusions: The current findings highlight the importance of CaMKII and CHOP signaling loop in ER stress mediated-apoptosis and LV hypertrophy and dysfunction induced by pressure overload. Therapeutic modulation of CHOP signaling may benefit patients with hypertension and LV hypertrophy and failure.
Author Disclosures: G. Cheng: None. X. Chen: None. L. Zhao: None. A. Samanta: None. M. Girgis: None. S. Ye: None. A. Davani: None. A. Browning: None. Y. Yang: None. J. Yang: None. A. Cantilena: None. J. Hauptman: None. R. Vincent: None. B. Dawn: None.
- © 2016 by American Heart Association, Inc.