Diabetes Blockade of Sevoflurane Postconditioning Is Not Restored by Insulin in the Rat Heart

Drenger, Benjamin; Ostrovsky, Israel A.; Barák, Michal; Nechemia-Arbely, Yael; Ziv, Ehud; Axelrod, Jonathan H.

doi:10.1097/aln.0b013e31820efafd

Cited by 79 publications

(51 citation statements)

References 44 publications

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“…However, in most cases, the cardioprotective effects of anaesthetics including isoflurane have been shown to be diminished or even abolished in hearts from individuals with diabetes [2,6]. Hyperglycaemia-induced oxidative and nitrosative stress, increased quantities of circulating inflammatory cytokines and dysfunction of mitochondrial K ATP channels are all plausible factors to explain the susceptibility of diabetic hearts to IRI [36][37][38][39].…”

Section: Discussionmentioning

confidence: 99%

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Cardioprotection from emulsified isoflurane postconditioning is lost in rats with streptozotocin-induced diabetes due to the impairment of Brg1/Nrf2/STAT3 signalling

Wang

Huang

et al. 2016

Clinical Science

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Isoflurane postconditioning (IsoPostC) attenuates myocardial ischaemia/reperfusion injury (IRI). Signal transducer and activator of transcription-3 (STAT3) is critical in ischaemic postconditioning cardioprotection, which can be regulated by the Brahma-related gene (Brg1) and nuclear factor-erythroid 2-related factor 2 (Nrf2), although they are both reduced in diabetic hearts. We hypothesized that reduced Brg1/Nrf2 and STAT3 activation may jeopardize IsoPostC-mediated cardioprotection in diabetic hearts. In the present study, Langendorff-perfused, non-diabetic (control) and 8-week-old streptozotocin-induced Type 1 diabetic rat hearts were subjected to 30 min of global ischaemia and 120 min of reperfusion without or with IsoPostC, which was achieved by administering emulsified isoflurane (2.0%, v/v) in Krebs-Henseleit (KH) solution immediately at the onset of reperfusion for 10 min and switching to KH solution perfusion alone thereafter. Cultured H9C2 cells were exposed to normal glucose (NG, 5.5 mM) or high glucose (HG, 30 mM) and subjected to hypoxia/reoxygenation (HR) in the presence or absence of IsoPostC. Diabetic rats displayed larger post-ischaemic myocardial infarction and more severe haemodynamic dysfunction, associated with increased myocardial oxidative stress and reduced cardiac Brg1, Nrf2 and STAT3 phosphorylation/activation (p-STAT3), compared with controls. These changes were reversed/prevented by IsoPostC in control but not in diabetic rats. In H9C2 cells exposed to NG but not HG, IsoPostC significantly attenuated HR-induced cellular injury and superoxide anion production with increased Brg1, Nrf2 and p-STAT3. These beneficial effects of IsoPostC were abolished by Brg1, Nrf2 or STAT3 gene knockdown. Brg1 or Nrf2 gene knockdown abolished IsoPostC-induced STAT3 activation. N-acetylcysteine restored Brg1, Nrf2 and p-STAT3, and IsoPostC-induced protection in H9C2 cells exposed to HG and HR. In conclusion, IsoPostC confers cardioprotection through Brg1/Nrf2/STAT3 signalling, and impairment of this pathway may be responsible for the loss of IsoPostC cardioprotection in diabetes.

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Section: Discussionmentioning

confidence: 99%

“…Reperfusion restores coronary flow, phenomenon is termed 'isoflurane postconditioning' (IsoPostC) [3]. However, the cardioprotective effects of volatile anaesthetic postconditioning are attenuated or abolished in rabbits [4] and mice [5] with hyperglycaemia or in individuals with diabetes [6], and the mechanism is unclear.…”

Section: Introductionmentioning

confidence: 99%

Cardioprotection from emulsified isoflurane postconditioning is lost in rats with streptozotocin-induced diabetes due to the impairment of Brg1/Nrf2/STAT3 signalling

Wang

Huang

et al. 2016

Clinical Science

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“…Blood glucose levels were controlled between 3.9 and 5.8 mmol/L with the following regimen: 3 U/d of intermediate-acting insulin was administered 48 h before cardiac ischemia, and 2U of short-acting insulin was administered 1 h before the experiment (Drenger et al, 2011). The Krebs-Henseleit solution was supplemented with the HIF-1α-specific inhibitor 2-methoxyestradiol 15 min prior to reperfusion (Si et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

“…However, the protective effects of SPC are lost under diabetic conditions (Drenger et al, 2011; Tai et al, 2012), and the mechanisms are poorly understood. It has been reported that under diabetic conditions, the hypoxia-inducible factor-1alpha (HIF-1α) signaling pathway is damaged (Heather and Clarke, 2011; Xiao et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Cobalt Chloride Upregulates Impaired HIF-1α Expression to Restore Sevoflurane Post-conditioning-Dependent Myocardial Protection in Diabetic Rats

Long

Xie

et al. 2017

Front. Physiol.

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Previous studies from our group have demonstrated that sevoflurane post-conditioning (SPC) protects against myocardial ischemia reperfusion injury via elevating the intranuclear expression of hypoxia inducible factor-1 alpha (HIF-1α). However, diabetic SPC is associated with decreased myocardial protection and disruption of the HIF-1 signaling pathway. Previous studies have demonstrated that cobalt chloride (CoCl2) can upregulate HIF-1α expression under diabetic conditions, but whether myocardial protection by SPC can be restored afterward remains unclear. We established a rat model of type 2 diabetes and a Langendorff isolated heart model of ischemia-reperfusion injury. Prior to reperfusion, 2.4% sevoflurane was used as a post-conditioning treatment. The diabetic rats were treated with CoCl2 24 h before the experiment. At the end of reperfusion, tests were performed to assess myocardial function, infarct size, mitochondrial morphology, nitric oxide (NO), Mitochondrial reactive oxygen species (ROS), mitochondrial respiratory function and enzyme activity, HIF-1α, vascular endothelial growth factor (VEGF) and endothelial NO synthase (eNOS) protein levels. In addition, myocardial protection by SPC was monitored after the blood glucose levels were lowered by insulin. The diabetic state was associated with deficient SPC protection and decreased HIF-1α expression. After treating the diabetic rats with CoCl2, SPC significantly upregulated the expression of HIF-1α, VEGF and eNOS, which markedly improved cardiac function, NO, mitochondrial respiratory function, and enzyme activity and decreased the infarction areas and ROS. In addition, these effects were not influenced by blood glucose levels. This study proved that CoCl2activates the HIF-1α signaling pathway, which restores SPC-dependent myocardial protection under diabetic conditions, and the protective effects of SPC were independent of blood glucose levels.

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“…The restoration of cardioprotection from ischaemic postconditioning with return to normoglycaemia, through transplantation of islet cells, has been identified in a type 1 diabetic mouse model study [116]. In a separate rat study, however, insulin pretreatment had very different findings, with no restoration of cardioprotective effects from ischaemic postconditioning [139]. …”

Section: Difficulties In Clinical Translation Of Ischaemic Conditionimentioning

confidence: 99%

Remote ischaemic conditioning in the context of type 2 diabetes and neuropathy: the case for repeat application as a novel therapy for lower extremity ulceration

Epps

Smart

2016

Cardiovasc Diabetol

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An emerging treatment modality for reducing damage caused by ischaemia–reperfusion injury is ischaemic conditioning. This technique induces short periods of ischaemia that have been found to protect against a more significant ischaemic insult. Remote ischaemic conditioning (RIC) can be administered more conveniently and safely, by inflation of a pneumatic blood pressure cuff to a suprasystolic pressure on a limb. Protection is then transferred to a remote organ via humoral and neural pathways. The diabetic state is particularly vulnerable to ischaemia–reperfusion injury, and ischaemia is a significant cause of many diabetic complications, including the diabetic foot. Despite this, studies utilising ischaemic conditioning and RIC in type 2 diabetes have often been disappointing. A newer strategy, repeat RIC, involves the repeated application of short periods of limb ischaemia over days or weeks. It has been demonstrated that this improves endothelial function, skin microcirculation, and modulates the systemic inflammatory response. Repeat RIC was recently shown to be beneficial for healing in lower extremity diabetic ulcers. This article summarises the mechanisms of RIC, and the impact that type 2 diabetes may have upon these, with the role of neural mechanisms in the context of diabetic neuropathy a focus. Repeat RIC may show more promise than RIC in type 2 diabetes, and its potential mechanisms and applications will also be explored. Considering the high costs, rates of chronicity and serious complications resulting from diabetic lower extremity ulceration, repeat RIC has the potential to be an effective novel advanced therapy for this condition.

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Diabetes Blockade of Sevoflurane Postconditioning Is Not Restored by Insulin in the Rat Heart

Cited by 79 publications

References 44 publications

Cardioprotection from emulsified isoflurane postconditioning is lost in rats with streptozotocin-induced diabetes due to the impairment of Brg1/Nrf2/STAT3 signalling

Cardioprotection from emulsified isoflurane postconditioning is lost in rats with streptozotocin-induced diabetes due to the impairment of Brg1/Nrf2/STAT3 signalling

Cobalt Chloride Upregulates Impaired HIF-1α Expression to Restore Sevoflurane Post-conditioning-Dependent Myocardial Protection in Diabetic Rats

Remote ischaemic conditioning in the context of type 2 diabetes and neuropathy: the case for repeat application as a novel therapy for lower extremity ulceration

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