Reduction of cold ischemia-reperfusion injury by graft-expressing clusterin in heart transplantation.

Abstract

BACKGROUND:

Cold ischemia-reperfusion injury (IRI) is a major factor for early graft dysfunction and is associated with rejection episodes in heart transplantation. Clusterin (CLU) is a cytoprotective protein with chaperone activity. This study was designed to examine the impact of donor-expressing CLU on cold IRI.

METHODS:

Donor hearts from wild-type C57BL/6J (H-2(b); B6 WT) vs CLU knockout C57BL/6J (H-2(b); B6 KO) mice were stored at 4°C for 8 hours, followed by heterotopic transplantation to B6 WT mice. The functional recovery of heart grafts was determined by scoring palpation, and tissue injury was determined by release of creatine kinase (CK) and lactate dehydrase (LDH) and also by histology.

RESULTS:

Heart cells constitutively expressed CLU, and mature CLU protein was localized mostly in the endothelium as well as on the cell surface of cardiac myocytes. As compared with CLU-deficient hearts, WT hearts were more resistant to cold injury during cold preservation, and had a better functional recovery after prolonged cold preservation and transplantation. The improved graft function of CLU-expressing grafts correlated significantly with reduced neutrophil infiltration and cardiac injury, including myocytic apoptosis and necrosis. Furthermore, in vitro examination showed that ectopic expression of CLU in cultured myocytes increased cell membrane stability after exposure to cold temperature and prevented cell death.

CONCLUSIONS:

CLU expression renders donor hearts resistance to cold IRI in transplantation, suggesting that upregulation of CLU expression in donor hearts may have potential for protecting heart grafts from cold IRI.

• Authors: Shuyuan Li, Qiunong Guan, Zhishui Chen, Martin E Gleave, Christopher Y C Nguan, Caigan Du
• Journal: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation (J Heart Lung Transplant) Vol. 30 Issue 7 Pg. 819-26 (Jul 2011) ISSN: 1557-3117 [Electronic] United States
• PMID: 21515078 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Clusterin

Topics

• Animals
• Cell Death
• Clusterin (metabolism)
• Cold Ischemia (adverse effects)
• Disease Models, Animal
• Graft Rejection
• Heart Transplantation
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Reperfusion Injury (prevention & control)
• Myocardium (metabolism)
• Myocytes, Cardiac (metabolism)
• Reperfusion Injury (prevention & control)