Abstract 16169: The Unfolded Protein Response in Cardiac Remodeling: XBP1s-induced Hypertrophy
Background: Hallmarks of pathological cardiac remodeling include myocyte hypertrophy and death, which together contribute to systolic dysfunction and clinical heart failure. Mechanisms governing pathogenesis remain obscure, and as a result, efficacy of clinical therapies is disappointing. During cardiac remodeling, the global architecture of the myocyte is refashioned, and accumulating evidence implicates proteotoxicity in disease pathogenesis. Protein misfolding induces the Unfolded Protein Response (UPR), comprising three distinct signaling cascades which enhance protein folding, eliminate terminally misfolded proteins, and induce apoptosis if the cell is beyond repair. Among these pathways, the transcription factor XBP1s participates in cardiomyocyte apoptosis in vitro. Yet, the role of XBP1s in cardiac remodeling in vivo is unknown.
Methods and Results: To test the role of XBP1s in hypertrophic remodeling, we expressed XBP1s in neonatal rat ventricular myocytes using lentiviral vectors. Forced expression of XBP1s induced hypertrophic growth which was amplified on exposure to phenylephrine. To test the function of XBP1s in vivo, we engineered a transgenic mouse with Xbp1s expressed under the control of tetracycline-responsive elements. By breeding these animals to αMHC-tTA transgenic mice, the induction of XBP1s expression in cardiomyocytes is manipulated by doxycycline (Tet-off). Robust induction of XBP1s expression was triggered by doxycycline removal for 4 weeks, and multiple XBP1s downstream targets were induced. Transgenic hearts were characterized by moderate hypertrophy without significant changes in ventricular chamber size or contractile performance. To address the role of XBP1s in load-induced hypertrophy, we subjected animals to thoracic aortic constriction (TAC). Here, we found that TAC-induced cardiac hypertrophy and fetal gene reactivation were significantly amplified in XBP1s transgenics relative to wild-type. TAC-stressed transgenic hearts also manifested deterioration in systolic function relative to wild-type.
Conclusions: XBP1s, one of the three arms of the UPR, promotes cardiac hypertrophy and the transition to failure.
- © 2010 by American Heart Association, Inc.