Publications

Mitochondrial integrity during early reperfusion in an isolated rat heart model of donation after circulatory death—consequences of ischemic duration

December 21, 2018

Sarah Longnus

BACKGROUND: Cardioprotection and graft evaluation after ischemia-reperfusion (IR) are essential in facilitating heart transplantation with donation after circulatory death. Given the key role of mitochon- dria in IR, we aimed to investigate the tolerance of cardiac mitochondria to warm, global ischemia and to determine the predictive value of early reperfusion mitochondria-related parameters for post-ische- mic cardiac recovery.
METHODS: Isolated, working rat hearts underwent 0, 21, 24, 27, 30, or 33 minutes of warm, global ischemia, followed by 60 minutes of reperfusion. Functional recovery (developed pressure£heart rate) was determined at 60 minutes of reperfusion, whereas mitochondrial integrity was measured at 10 minutes of reperfusion.
RESULTS: Functional recovery at 60 minutes of reperfusion decreased with ≥ 27 minutes of ischemia vs no ischemia (n = 7−8/group; p < 0.01). Cytochrome c, succinate release, and mitochondrial Ca2+ con- tent increased with ≥ 27 minutes of ischemia vs no ischemia (p < 0.05). Ischemia at ≥ 21 minutes decreased mitochondrial coupling, adenosine 50-triphosphate content, mitochondrial Ca2+ retention capacity, and increased oxidative damage vs no ischemia (p < 0.05). Reactive oxygen species (ROS) from reverse electron transfer increased with 21 and 27 minutes of ischemia vs no ischemia and 33 minutes of ischemia (p < 0.05), whereas ROS from forward electron transfer increased only with 33 minutes of ischemia vs no ischemia (p < 0.05). Mitochondrial coupling and adenosine 50-triphosphate content correlated positively and cytochrome c, succinate, oxidative damage, and mitochondrial Ca2+ content correlated negatively with cardiac functional recovery (p < 0.05). CONCLUSIONS: Mitochondrial dysfunction occurs with shorter periods of ischemia than cardiac dys- function. Mitochondrial coupling, ROS emission from reverse electron transfer, and calcium retention are particularly sensitive to early reperfusion injury, reflecting potential targets for cardioprotection.

Nitroglycerin limits infarct size through S-nitrosation of Cyclophilin D: A novel mechanism for an old drug

August 27, 2018

Ioanna Andreadou

Aims
Nitroglycerin (NTG) given prior to an ischemic insult exerts cardioprotective effects. However, whether administration of an acute low dose of NTG in a clinically relevant manner following an ischemic episode limits infarct size, has not yet been explored.
Methods and Results
Adult mice were subjected to acute myocardial infarction in vivo and then treated with vehicle or low dose NTG prior to reperfusion. This treatment regimen minimized myocardial infarct size without affecting hemodynamic parameters, but the protective effect was absent in mice rendered tolerant to the drug. Mechanistically, NTG was shown to nitrosate and inhibit cyclophilin D (CypD), and NTG administration failed to limit infarct size in CypD knockout mice. Additional experiments revealed lack of the NTG protective effect following genetic (knockout mice) or pharmacological inhibition (L-NAME treatment) of the endothelial nitric oxide synthase (eNOS). The protective effect of NTG was attributed to preservation of the eNOS dimer. Moreover, NTG retained its cardioprotective effects in a model of endothelial dysfunction (ApoE knockout) by preserving CypD nitrosation. Human ischemic heart biopsies revealed reduced eNOS activity and exhibited reduced CypD nitrosation.
Conclusions
Low dose NTG given prior to reperfusion reduces myocardial infarct size by preserving eNOS function, and the subsequent eNOS-dependent S-nitrosation of cyclophilin D, inhibiting cardiomyocyte necrosis. This novel pharmacological action of NTG warrants confirmation in clinical studies, although our data in human biopsies provide promising preliminary results.

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