Journal
TRANSPLANT IMMUNOLOGY
Volume 37, Issue -, Pages 40-45Publisher
ELSEVIER
DOI: 10.1016/j.trim.2016.05.001
Keywords
Cardiac transplantation; Ischemia-reperfusion; Apoptosis; Necroptosis; Simvastatin
Categories
Funding
- Academy of Finland
- Sigrid Juselius Foundation
- Helsinki University Central Hospital Research Funds
- Finnish Cultural Foundation
- Finnish Foundation for Cardiovascular Research
- Emil Aaltonen Foundation
- Research and Science Foundation of Farmos
- Aarne Koskelo Foundation
- Paavo Ilmari Ahvenainen Foundation
- Sirpa and Markku Jalkanen Foundation
- Finnish Transplantation Society
- Paivikki and Sakari Sohlberg Foundation
- Finnish Society of Angiology
- Paulo Foundation
- Maud Kuistila Foundation
- Ida Montin Foundation
Ask authors/readers for more resources
Background: In transplantation-associated ischemia/reperfusion injury (Tx-IRI), tumor necrosis factor alpha and damage-associated molecular patterns promote caspase-8 and -9 apoptotic and receptor-interacting protein kinase-1 and-3 (RIPK1/3) necroptotic pathway activation. The extent of cell death and the counterbalance between apoptosis and regulated necrosis eventually determine the immune response of the allograft. Although simvastatin prevents Tx-IRI, its role in apoptotic and necroptotic activity remains unsolved. Methods: Rat allograft donors and recipients were treated with a single-dose of simvastatin 2 h prior to allograft procurement and reperfusion, respectively. Intragraft caspase-3, -8, and -9 and RIPK1 and-3 mRNA expression was analysed by quantitative RT-PCR and protein activity measured by immunohistochemistry and luminescent assays 6 h after reperfusion. Lactate and lactate dehydrogenase (LDH) levels were analysed from allograft recipient and from hypoxic endothelial cell cultures having treated with activated simvastatin. Results: When compared to without cold ischemia, prolonged 4-hour cold ischemia significantly enhanced intragraft mRNA expression of caspase-3 and-9, and RIPK1 and -3, and elevated protein activity of caspase-9 and RIPK1 in the allografts. Simvastatin pretreatment decreased mRNA expression of caspase-3 and -9, and RIPK1 and-3 and protein activity of caspase-9 and RIPK1 in the allografts. Intragraft caspase-8 mRNA expression remained constant regardless of cold ischemia or simvastatin pretreatment. Simvastatin pretreatment attenuated lactate and LDH levels, both in the allograft recipients and in hypoxic endothelial cell cultures. Conclusions: The beneficial effects of simvastatin pretreatment in cardiac allograft IRI may involve prevention of apoptosis and necroptosis. (C) 2016 Elsevier B.V. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available