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

Abstract

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.

Nuclear factor erythroid 2-related factor 2 enhances carcinogenesis by suppressing apoptosis and promoting autophagy in nickel-transformed cells

“…Recent reports describe a relationship between Nrf2 and Stat3. For example, the Nrf2-mediated upregulation of Stat3 has cardioprotective effects in a streptozotocin-induced diabetes model (57). Stat3 and Nrf2 promote the proliferation of neural stem cells (58) and inhibit virally induced inflammatory responses (59).…”

Effects of Cardiovascular Risk Factors on Cardiac STAT3

“…In an animal model of STZ-induced type I diabetes, after 30 min ischaemia and 2 h reperfusion there was a significant reduction in phosphorylated STAT3 (Tyr705) levels in the diabetic group compared to the nondiabetic control group (tissue samples were collected from the ischaemic zone of the myocardium) [ 93 ]. This reduction of post-ischaemic STAT3 phosphorylation and/or activation due to diabetes was confirmed by several studies of another research group in the ischaemic tissue as well as in whole heart or ventricular tissue samples [ 29 , 31 , 33 , 92 , 94 ]. In addition, the phosphorylated STAT3 (Tyr705) and total STAT3 levels were significantly reduced in a type II diabetes model, i.e., in isolated perfused hearts of leptin receptor null, homozygous db/db mice subjected to ischaemia/reperfusion compared to wild-type hearts subjected to ischaemia/reperfusion [ 95 ].…”

“…In H9c2 cells subjected to high glucose conditions (25 mM glucose), the post-ischaemic STAT3 phosphorylation and activation (at Ser727 and Tyr705 sites) were significantly lower [ 29 , 32 ]. Similarly, exposure of isolated adult rat ventricular cardiomyocytes to high glucose conditions also resulted in reduced post-ischaemic STAT3 activation (at Tyr705 site) [ 33 , 92 ].…”

Discovery of Novel Small-Molecule Inducers of Heme Oxygenase-1 That Protect Human iPSC-Derived Cardiomyocytes from Oxidative Stress

“…HMOX1 expression has previously been reported to be dependent on cellular metabolic state, with expression significantly reduced in H9c2 cells treated under high-glucose conditions (Li et al, 2015;Gao et al, 2016). Diabetic hyperglycemia has also been shown to block the cardioprotective effects of anesthetic preconditioning in vitro and in vivo by impairing the Nrf2 signaling response (Li et al, 2015;Canfield et al, 2016;Gao et al, 2016;Wang et al, 2016b). Differences in metabolism between hiPSC-CMs and H9c2 cells probably account for the observed differences in protection between the cell types for the hit compounds and demonstrates the relevance of the cell model and culture conditions for hit identification.…”