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Unfolded protein response (UPR)-mediated apoptosis plays a pivotal role in ischemia-reperfusion injury. Sodium 4-phenylbutyrate (PBA) has been reported to act as a chemical chaperone inhibiting UPR-mediated apoptosis triggered by ischemia in various organs other than the heart. Therefore we investigated whether PBA reduces UPR-mediated apoptosis and protects against myocardial ischemia-reperfusion injury in mice.
C57BL/6 mice were subjected to 30 minutes LAD ischemia followed by reperfusion. PBA (100 mg/kg) or PBS (control) was administrated intraperitoneally just before ischemia. Apoptosis, infarct size and tissue protein levels of Grp78 and caspase-12 (UPR-mediated apoptosis-associated protein) were evaluated by TUNEL, TTC stain and western blot analyses, respectively, at 48 hours after ischemia (n = 5 for each group). Echocardiography was performed at 3 weeks after ischemia and the survival ratio was observed (n = 9 for each group).
Compared with PBS, PBA reduced apoptotic cells (30.8 ± 0.2% vs 20.5 ± 0.5%, P < 0.05) and infarct size (32.0 ± 3.8% vs 13.0 ± 2.1%, P < 0.01) after ischemia-reperfusion. Grp78 and caspase-12 were increased in mice with PBS, but PBA attenuated the increase in Grp78 (P < 0.05) and caspase-12 (P < 0.05). PBA inhibited the deterioration of cardiac parameters including LVEDD (3.35 ± 0.08 mm vs 2.74 ± 0.11 mm, P < 0.01), LVESD (2.30 ± 0.08 mm vs 1.54 ± 0.12 mm, P < 0.01), and %FS (31.3 ± 2.2% vs 39.4 ± 2.2%, P < 0.05). All mice with PBA survived, but 33% animals with PBS died.
PBA maintained cardiac function and improved survival ratio after myocardial ischemia-reperfusion by reducing UPR-mediated apoptosis in mice.