Publications

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.

Cardioprotective reperfusion strategies differentially affect mitochondria:studies in an isolated rat heart model of donation after circulatory death (DCD)

July 18, 2018

Sarah L. Longnus

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 pre-ischemic 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 three reperfusion strategies: mild hypothermia, mechanical post-conditioning 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 three strategies improve oxygen-consumption-cardiac-work coupling and increase tissue ATP content, in parallel with increased functional recovery. These reperfusion strategies, however, differentially affect mitochondria; mild hypothermia also increases phosphocreatine content, while mechanical post-conditioning stimulates mitochondrial complex I activity and reduces cytochrome c release (marker of mitochondrial damage), whereas hypoxia up-regulates the expression of Pgc-1α (regulator of mitochondrial biogenesis). Characterisation of the role of mitochondria in cardioprotective reperfusion strategies should aid in the identification of new, mitochochondrial-based therapeutic targets and the development of effective reperfusion strategies that could ultimately facilitate DCD heart transplantation.

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