Original Contribution
Protective effects of hemoglobin-based oxygen carrier given to isolated heart during ischemia via attenuation of mitochondrial oxidative damage

https://doi.org/10.1016/j.freeradbiomed.2010.01.027Get rights and content

Abstract

Ischemia/reperfusion (I/R) injury is harmful to the cardiovascular system and responsible for mitochondrial oxidative stress, which will in turn aggravate cardiac dysfunction. This study was designed to investigate the protective effect of a hemoglobin-based oxygen carrier (HBOC) on I/R heart and to elucidate the potential mechanism. Isolated Sprague–Dawley rat hearts were perfused in Langendorff mode. After 30-min basal perfusion, warm ischemia (37°C) or hypothermic storage (4°C) was performed and followed by 2-h reperfusion. The results of our study reveal that HBOC provides a profound protection against cardiac I/R injury as evidenced by significantly improved cardiac function and decreased myocardial infarction, necrosis, and apoptosis. In addition to more oxygen supply to the myocardium, the cardioprotection of HBOC was closely related to well-preserved mitochondrial redox potential, significantly elevated mitochondrial superoxide dismutase activity, and decreased mitochondrial hydrogen peroxide and malondialdehyde formation, which indicated that the I/R-induced mitochondrial oxidative damage was remarkably attenuated. Furthermore, the elevated mitochondrial function and unchanged mitochondrial structure provide additional evidence of the prominent role of HBOC in mitochondrial preservation. In conclusion, our results demonstrate the cardioprotective effect of HBOC on I/R heart and reveal that this protection was mediated in large part by attenuation of mitochondrial oxidative damage.

Section snippets

Materials and methods

All experiments were approved by the Institutional Animal Care and Use Committee of Sichuan University and conformed to the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publication No. 85-23, revised 1996).

Oxygen releasing capacity of HBOC

As shown in Fig. 2A, the O2 releasing capacity of 0. 1 g Hb/dl HBOC was nearly 1.5-fold higher than that of the STS alone (206.70 ± 14.20 vs 139.27 ± 10.83 mm Hg/g wet wt, P < 0.05). Consistently, the cardiac lactic acid release of the WI + HBOC and HS + HBOC groups hearts was largely inhibited compared with the WI and HS groups (P < 0.05 and P < 0.05, respectively, Fig. 2B).

HBOC improves cardiac LV function recovery after I/R

Measures reflecting LV contractile function were similar under basal conditions. During the reperfusion, the WI + HBOC group hearts

Discussion

This study provides distinct evidence that HBOC significantly improved cardiac function and decreased myocardial infarct size, thus exhibiting profound protection against myocardial I/R injury. Such protection was further proven by the marked decreases in myocardial necrosis and apoptosis. To reveal the underlying mechanism, we investigated the redox status of the mitochondria in these hearts. The results clearly showed that the mitochondrial Eh was well preserved by HBOC, which was accompanied

Acknowledgments

This study was supported by grants from the National Nature Science Foundation of China (30772084 and 30828030 to Dr. Jin Liu and 30801083 to Dr. Ronghua Zhou), the Key Project of the Chinese Ministry of Education (106132 to Dr. Ke Dian), and the 973 Program (2005 CB522601 to Dr. Jin Liu). The authors thank Professor Chengmin Yang for technical assistance.

References (30)

  • D'AgnilloF. et al.

    Polyhemoglobin–superoxide dismutase–catalase as a blood substitute with antioxidant properties

    Nat. Biotechnol.

    (1998)
  • GannonC.J. et al.

    Severe anemia after gastrointestinal hemorrhage in a Jehovah's Witness: new treatment strategies

    Crit. Care Med.

    (2002)
  • LiT. et al.

    method for purification and viral inactivation of human placenta hemoglobin

    Artif. Cells Blood Substit. Immobil. Biotechnol.

    (2006)
  • McNeilC.J. et al.

    Hypotensive resuscitation using a polymerized bovine hemoglobin-based oxygen-carrying solution (HBOC-201) leads to reversal of anaerobic metabolism

    J. Trauma

    (2001)
  • DeemS. et al.

    Effects of S-nitrosation and cross-linking of hemoglobin on hypoxic pulmonary vasoconstriction in isolated rat lungs

    Circ. Res.

    (2002)
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