Sevoflurane postconditioning attenuates cardiomyocyte hypoxia/reoxygenation injury via restoring mitochondrial morphology

Abstract

BackgroundAnesthetic postconditioning is a cellular protective approach whereby exposure to a volatile anesthetic renders a tissue more resistant to subsequent ischemic/reperfusion event. Sevoflurane postconditioning (SPostC) has been shown to exert cardioprotection against ischemia/reperfusion injury, but the underlying mechanism is unclear. We hypothesized that SPostC protects cardiomyocytes against hypoxia/reoxygenation (H/R) injury by maintaining/restoring mitochondrial morphological integrity, a critical determinant of cell fate.MethodsPrimary cultures of neonatal rat cardiomyocytes (NCMs) were subjected to H/R injury (3 h of hypoxia followed by 3 h reoxygenation). Intervention with SPostC (2.4% sevoflurane) was administered for 15 min upon the onset of reoxygenation. Cell viability, Lactate dehydrogenase (LDH) level, cell death, mitochondrial morphology, mitochondrial membrane potential and mitochondrial permeability transition pore (mPTP) opening were assessed after intervention. Mitochondrial fusion and fission regulating proteins (Drp1, Fis1, Mfn1, Mfn2 and Opa1) were assessed by immunofluorescence staining and western blotting was performed to determine the level of protein expression.ResultsCardiomyocyte H/R injury resulted in significant increases in LDH release and cell death that were concomitant with reduced cell viability and reduced mitochondrial interconnectivity (mean area/perimeter ratio) and mitochondrial elongation, and with reduced mitochondrial membrane potential and increased mPTP opening. All the above changes were significantly attenuated by SPostC. Furthermore, H/R resulted in significant reductions in mitochondrial fusion proteins Mfn1, Mfn2 and Opa1 and significant enhancement of fission proteins Drp1 and Fis1. SPostC significantly enhanced Mfn2 and Opa1 and reduced Drp1, without significant impact on Mfn1 and Fis1.ConclusionsSevoflurane postconditioning attenuates cardiomyocytes hypoxia/reoxygenation injury (HRI) by restoring mitochondrial fusion/fission balance and morphology.

Novel insights into the role of mitochondrial fusion and fission in cardiomyocyte apoptosis induced by ischemia/reperfusion

“…It is confirmed that I/R down‐regulates the expression of mitochondrial fusion proteins including Mfn1, Mfn2, and Opa1, disrupts mitochondrial fusion and increases cardiomyocyte apoptosis (Cellier et al, ; Dong, Chen, et al, ; Yang et al, ; Yu et al, , ; Zhao et al, ). Multiple lines of evidence suggest that inhibition of endogenous fusion proteins enhances I/R‐induced cardiomyocyte apoptosis, and up‐regulation of fusion proteins suppresses I/R‐induced cardiomyocyte apoptosis.…”

“…Under I/R conditions, mitochondrial fission plays a key role in regulating cardiomyocyte apoptosis. Mitochondrial fission proteins including Drp1, Fis1, MFF, Mtfr1 as well MTP18 are up‐regulated in cardiomyocytes exposed to I/R, followed by the increase of mitochondrial fission and cell apoptosis (Long et al, ; Wang et al, ; Wang, Gan, et al, ; Yang et al, ; Yu et al, , ; Zaja et al, ). And I/R also stimulates the translocation of Drp1 from the cytosol to mitochondria (Cellier et al, ; Din et al, ; Ikeda et al, ).…”

“…Besides regulation of mitochondrial fission proteins, I/R can decrease fusion protein levels (Mfn1, Mfn2 and Opa1) (Cellier et al, ; Ong et al, ; Yu et al, ). MiR‐140 could suppress the expression of Mfn1 and this inhibitory effect is dependent on the 3′UTR of Mfn1 mRNA (Li et al, ).…”

Deferoxamine-activated hypoxia-inducible factor-1 restores cardioprotective effects of sevoflurane postconditioning in diabetic rats

“…31,34 A previous study showed that impairment of HIF-1 can lead to a surge in ROS generation. 31,34 A previous study showed that impairment of HIF-1 can lead to a surge in ROS generation.…”

Sevoflurane postconditioning protects the myocardium against ischemia/reperfusion injury via activation of the JAK2–STAT3 pathway

“…In addition, our latest studies have shown that mitochondria are the terminal operating apparatuses of S-post mediated cardioprotection (Yu et al, 2016a, 2016b). Mitochondria are major sources of ROS during myocardial I/R.…”