Abstract P156: IRE1α Activity Is Abbreviated in Myocytes
BACKGROUND: A unifying feature of Ischemia/reperfusion injury, myocardial infarction and heart failure is disruption of endo(sarco)plasmic reticulum homeostasis and activation of the intracellular signaling pathway known as “ER Stress” or “Unfolded Protein Response” (UPR). UPR signaling is activated through three ER Stress sensor proteins, including IRE1α. IRE1α can, through direct interaction, induce adaptive or apoptotic signaling programs. Although ER stress signaling is known to be active following various cardiac injuries, it is unknown whether IRE1α contributes to an adaptive or apoptotic program. We sought to characterize the functional impact of IRE1-mediated UPR signaling in cardiomyocytes.
HYPOTHESIS: IRE1α-mediated UPR signaling contributes to cardiac hypertrophy or cell death in response to pathological stresses. METHOD: NRVM were treated with adenovirus-mediated IRE1α-myc overexpression. Protein and RNA were harvested two and five days following treatment and IRE1α activation, activity and downstream signaling was monitored by PCR, qPCR, and immunoblot.
RESULTS: Ectopic expression led to robust phosphor-IRE1α Ser724 and IRE1α RNase activity toward Xbp-1. BiP and EDEM expression was induced, indicative of adaptive UPR signaling. Apoptotic UPR signaling was not induced (CHOP expression). Surprisingly, IRE1α activity and downstream signaling was transient. After five days, both IRE1α RNase activity and downstream signaling were extinguished, despite continued robust IRE1α protein expression and activation (phospho-Ser724).
CONCLUSION: NRVM possess uncharacterized intrinsic mechanisms to protect against unwarranted IRE1α signaling.
- © 2011 by American Heart Association, Inc.