Mitochondrial permeability transition-pore inhibition enhances functional recovery after long-time hypothermic heart preservation.
OBJECTIVES: Long-time preservation of the donor heart before transplantation is associated with mitochondrial damages resulting in functional deterioration after transplantation, although the exact mechanism behind this is still uncertain. Here, we have demonstrated the opening of a nonspecific pore in the inner membrane of the mitochondria, the mitochondrial permeability transition pore (PTP), as one of the reasons responsible for this functional deterioration. METHODS: After 30 minutes of perfusion with the Krebs Henseleit buffer at 37 degrees C in working mode, hearts from Wistar rats were arrested with ice-cold St. Thomas cardioplegic solution and preserved University of Wisconsin solution at 4 degrees C with or without inhibiting the PTP with cyclosporin A (CsA) (0.2 microM). After 12 hours, the hearts were reperfused for 60 minutes at 37 degrees C with or without perfusing the hearts during first 15 minutes of reperfusion with PTP openers lonidamine (30 microM) or atractyloside (20 microM). RESULTS: Inhibiting PTP with CsA resulted in (a) significant recovery of cardiac functions, (b) well-preserved myocardial adenosine triphosphate (ATP) levels (P<0.001), (c) less myocardial water content (P<0.01), (d) less mitochondrial swelling and cytochrome C release, and (e) up-regulation of Bcl-2 expression compared with the control hearts without PTP inhibition. These effects are completely inhibited on opening the PTP before preservation, resulting in poor recovery of cardiac functions, loss of myocardial ATP, and severe mitochondrial swelling. CONCLUSION: The present study demonstrates the potential role of mitochondrial PTP after long- time hypothermic preservation of the heart, and therefore, regulation of PTP would prolong the preservation time of donor hearts.[1]References
- Mitochondrial permeability transition-pore inhibition enhances functional recovery after long-time hypothermic heart preservation. Rajesh, K.G., Sasaguri, S., Ryoko, S., Maeda, H. Transplantation (2003) [Pubmed]
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