Abstract 12879: C/ebp Homologous Protein Deficiency Attenuates Myocardial Ischemia-Reperfusion Injury by Inhibiting Endoplasmic Reticulum Stress-Induced Apoptosis and Inflammation
Myocardial ischemia-reperfusion (I/R) injury is currently problematic, but its molecular mechanisms have not been fully clarified. In general, various pathophysiological stimuli trigger endoplasmic reticulum (ER) stress, and excessive response against ER stress is thought to promote apoptosis through activating C/EBP homologous protein (CHOP)-mediated pathway. Therefore, we focused our investigation on the role of CHOP in myocardial I/R injury. Wild-type (WT) and CHOP deficient (CHOP−/−) mice were subjected to 50 min of myocardial ischemia followed by reperfusion. ER stress as assessed by induction of CHOP, phosphorylation of eIF2α and splicing of XBP1 was rapidly and significantly increased at 30 min after reperfusion in WT mice compared with sham-operated mice (p<0.05). The injury size was markedly reduced in CHOP−/− mice at 8 h after reperfusion compared with WT mice (13.9±1.3% versus 44.8±1.7%, p<0.01), accompanied with decreasing number of TUNEL-positive cardiomyocytes (1.5±0.2% versus 10.4±1.9%, p<0.01). Interestingly, expression of pro-inflammatory cytokines and chemokines such as TNF-α, IL-1β, IL-6, MIP-2/CXCL2 and MCP-1/CCL2, and subsequent infiltration of inflammatory cells were also reduced in CHOP−/− mice compared with WT mice (p<0.05). Moreover, in vitro analysis showed that IL-6 expression was enhanced after simultaneous stimulation of LPS and thapsigargin, a potent ER stress inducer, compared with LPS alone in WT cardiomyocytes (p<0.01), but not in CHOP−/− cardiomyocytes (p=0.9). Finally, we examined whether ROS overproduction after reperfusion causes ER stress and subsequent myocardial damage. Intravenous administration of edaravone, a free radical scavenger, just before reperfusion significantly suppressed the ROS overproduction, XBP1 splicing and CHOP induction, followed by reduced injury size in WT mice. These findings suggest that ER stress-induced CHOP-mediated pathway, which is partially activated by ROS overproduction after reperfusion, exacerbates myocardial I/R injury by inducing not only cardiomyocyte apoptosis but also tissue inflammation. CHOP and/or its-induced molecules may be targets to develop new cardioprotective strategies against myocardial I/R injury.
- © 2010 by American Heart Association, Inc.