Abstract 15861: ER Stress and ATF3 Play Essential Roles in the Cardioprotective Effects of the Late Phase of Ischemic Preconditioning
Ischemic preconditioning (PC), elicited by brief preceding bouts of ischemia has been shown to protect the myocardium from infarction. Previous studies show that ischemia/reperfusion injury induces ER stress in the heart, suggesting that the cardioprotective effects of ischemic PC may be mediated in part by the unfolded protein response (UPR) to transient ischemia. To examine the role of ER stress in ischemic PC, adult male C57BL/6 mice were subjected to 6 cycles of coronary occlusion in situ followed by 4 min of reperfusion per cycle. In comparison with sham-operated hearts, reperfusion for 30 min after ischemic PC led to a 2.4-fold and 13-fold increase in the nuclear abundance of the transcription factors ATF6 (n=4, p<0.004) and ATF3 (n=4, p<0.001), respectively. Reperfusion for 24 h after PC induced a 2.6-fold (n=4; p<0.03) increase in the myocardial abundance of the transcription factor ATF4 and a 1.5-fold increase (n=4; p<0.05) in ER-resident proteins identified by the KDEL localization sequence. In WT, untreated mice, the anterior LV infarct size after 30 min of ischemia followed by 24 h of reperfusion was 63.4 ± 1.5 % of the risk region. In hearts subjected to ischemic PC, the infarct size was reduced to 33.2 ± 2.0 %. Intravenous infusion of 300 mg/kg 4-phenylbutryic acid (PBA), a chemical chaperone that assists protein folding, 90 min before PC abolished the infract-sparing effects of ischemic PC (infarct size = 63.5 ± 2.8 % of the risk region; n=6). The cardioprotective effects of ischemic PC were also abolished in ATF3-null mice (infarct size = 66.1 ± 3.1 % of the risk region; n=12). Collectively, these observations indicate that ischemic PC activates components of the UPR and that ER stress is essential for the cardioprotective effects of ischemic PC. The stress-activated transcription factor ATF3 appears to play an obligatory role in ischemic PC-mediated cardioprotection.
- © 2010 by American Heart Association, Inc.