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Cardioprotective reperfusion strategies differentially affect mitochondria: Studies in an isolated rat heart model of donation after circulatory death (DCD)
Author(s) -
Sanz Maria N.,
Farine Emilie,
Niederberger Petra,
MéndezCarmotalia,
Wyss Rahel K.,
Arnold Maria,
Gulac Patrik,
Fiedler Georg M.,
Gressette Mélanie,
Garnier Anne,
Carrel Thierry P.,
Tevaearai Stahel Hendrik T.,
Longnus Sarah L.
Publication year - 2019
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15024
Subject(s) - mitochondrial biogenesis , cardioprotection , reperfusion injury , medicine , mitochondrion , ischemia , hypothermia , circulatory system , transplantation , hypoxia (environmental) , mitochondrial permeability transition pore , pharmacology , cardiology , programmed cell death , apoptosis , microbiology and biotechnology , biology , biochemistry , chemistry , oxygen , organic chemistry
Donation after circulatory death (DCD) holds great promise for improving cardiac graft availability; however, concerns persist regarding injury following warm ischemia, after donor circulatory arrest, and subsequent reperfusion. Application of preischemic treatments is limited for ethical reasons; thus, cardioprotective strategies applied at graft procurement (reperfusion) are of particular importance in optimizing graft quality. Given the key role of mitochondria in cardiac ischemia–reperfusion injury, we hypothesize that 3 reperfusion strategies—mild hypothermia, mechanical postconditioning, and hypoxia, when briefly applied at reperfusion onset—provoke mitochondrial changes that may underlie their cardioprotective effects. Using an isolated, working rat heart model of DCD, we demonstrate that all 3 strategies improve oxygen‐consumption–cardiac‐work coupling and increase tissue adenosine triphosphate content, in parallel with increased functional recovery. These reperfusion strategies, however, differentially affect mitochondria; mild hypothermia also increases phosphocreatine content, while mechanical postconditioning stimulates mitochondrial complex I activity and reduces cytochrome c release (marker of mitochondrial damage), whereas hypoxia upregulates the expression of peroxisome proliferator‐activated receptor‐gamma coactivator (regulator of mitochondrial biogenesis). Characterization of the role of mitochondria in cardioprotective reperfusion strategies should aid in the identification of new, mitochondrial‐based therapeutic targets and the development of effective reperfusion strategies that could ultimately facilitate DCD heart transplantation.