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  • Open Access

Sodium 4-phenylbutylate protects against myocardial ischemia-reperfusion injury by reducing unfolded protein response-mediated apoptosis in mice

  • 1,
  • 2,
  • 2,
  • 1 and
  • 2
Critical Care201014 (Suppl 1) :P2

https://doi.org/10.1186/cc8234

  • Published:

Keywords

  • Ischemia
  • Western Blot Analysis
  • Apoptotic Cell
  • Pivotal Role
  • Cardiac Function

Introduction

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.

Methods

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).

Results

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.

Conclusions

PBA maintained cardiac function and improved survival ratio after myocardial ischemia-reperfusion by reducing UPR-mediated apoptosis in mice.
Figure 1
Figure 1

Phenylbutyrate reduced the unfolded protein response.

Authors’ Affiliations

(1)
Kanazawa University Hospital, Kanazawa, Japan
(2)
Kanazawa University Graduate School of Medical Science, Kanazawa, Japan

References

  1. Qi X, et al.: Mol Pharmacol. 2004, 66: 899-908. 10.1124/mol.104.001339View ArticleGoogle Scholar
  2. Vilatoba M: Surgery. 2005, 138: 342-351. 10.1016/j.surg.2005.04.019View ArticleGoogle Scholar

Copyright

© BioMed Central Ltd. 2010

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