Research Article: Sevoflurane postconditioning is not mediated by ferritin accumulation and cannot be rescued by simvastatin in isolated streptozotocin-induced diabetic rat hearts

Date Published: January 25, 2019

Publisher: Public Library of Science

Author(s): Hilbert Grievink, Natalia Kuzmina, Mordechai Chevion, Benjamin Drenger, Meijing Wang.


Sevoflurane postconditioning (sevo postC) is an attractive and amenable approach that can protect the myocardium against ischemia/reperfusion (I/R)-injury. Unlike ischemic preconditioning (IPC), sevo postC does not require additional induced ischemic periods to a heart that is already at risk. IPC was previously shown to generate myocardial protection against I/R-injury through regulation of iron homeostasis and de novo ferritin synthesis, a process found to be impaired in the diabetic state. The current study investigated whether alterations in iron homeostasis and ferritin mRNA and protein accumulation are also involved in the cardioprotective effects generated by sevo postC. It was also investigated whether the protective effects of sevo postC in the diabetic state can be salvaged by simvastatin, through inducing nitric oxide (NO) bioavailability/activity, in isolated streptozotocin (STZ)-induced diabetic hearts (DH). Isolated rat hearts from healthy Controls and diabetic animals were retrogradely perfused using the Langendorff configuration and subjected to prolonged ischemia and reperfusion, with and without (2.4 and 3.6%) sevo postC and/or pre-treatment with simvastatin (0.5 mg/kg). Sevo postC significantly reduced infarct size and improved myocardial function in healthy Controls but not in isolated DH. The sevo postC mediated myocardial protection against I/R-injury was not associated with de novo ferrtin synthesis. Furthermore, simvastatin aggravated myocardial injury after sevo postC in STZ-induced DHs, likely due to increasing NO levels. Despite the known mechanistic overlaps between PC and postC stimuli, distinct differences underlie the cardioprotective interventions against myocardial I/R-injury and are impaired in the DH. Sevo postC mediated cardioprotection, unlike IPC, does not involve de novo ferritin accumulation and cannot be rescued by simvastatin in STZ-induced DHs.

Partial Text

Myocardial ischemia reperfusion (I/R)-injury is a leading cause of perioperative morbidity and mortality. Protective interventions against I/R-injury include, ischemic-preconditioning (IPC) [1] and -postconditioning [2]. Pharmacological agents such as sevoflurane (sevo) can also trigger cardioprotection [3–7]. Distinct mechanistic overlaps can be achieved by pharmacological agents, such as sevo [8].

Average body weights (BW) and heart weights (HW) were not significantly different between the control animals (Mean ± SEM: BW; 309 ± 4 g, HW; 1.33 ± 0.02 g) and the STZ-induced diabetic animals (Mean ± SEM: BW; 307 ± 6 g, HW; 1.33 ±0.03 g), prior to the ex vivo perfusion experiments. Blood glucose levels, in the fed state, were significantly higher for STZ-induced diabetic animals (Mean ± SEM: 539 ± 12 mg/dL, p<0.01) compared to control animals (Mean ± SEM: 126 ± 3 mg/dL). In the clinical situation, the protective benefits of PC have not yet been realized, not at least because PC can only be implemented in the situations where the ischemic events can be predicted, which in the case of an acute MI is unattainable. Pharmacological postC with volatile anestetics, such as sevoflurane, is an attractive and amenable approach in cardiac surgery, as it can be administered at the onset of reperfusion and does not require additional ischemic periods to a heart that is already at risk.   Source: