Hydrogen Sulfide Preconditioning Protects Rat Liver against Ischemia/Reperfusion Injury by Activating Akt-GSK-3β Signaling and Inhibiting Mitochondrial Permeability Transition

Abstract

Hydrogen sulfide (H2S) is the third most common endogenously produced gaseous signaling molecule, but its impact on hepatic ischemia/reperfusion (I/R) injury, especially on mitochondrial function, remains unclear. In this study, rats were randomized into Sham, I/R, ischemia preconditioning (IPC) or sodium hydrosulfide (NaHS, an H2S donor) preconditioning groups. To establish a model of segmental (70%) warm hepatic ischemia, the hepatic artery, left portal vein and median liver lobes were occluded for 60 min and then unclamped to allow reperfusion. Preconditioning with 12.5, 25 or 50 μmol/kg NaHS prior to the I/R insult significantly increased serum H2S levels, and, similar to IPC, NaHS preconditioning decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the plasma and prevented hepatocytes from undergoing I/R-induced necrosis. Moreover, a sub-toxic dose of NaHS (25 μmol/kg) did not disrupt the systemic hemodynamics but dramatically inhibited mitochondrial permeability transition pore (MPTP) opening and thus prevented mitochondrial-related cell death and apoptosis. Mechanistic studies revealed that NaHS preconditioning markedly increased the expression of phosphorylated protein kinase B (p-Akt), phosphorylated glycogen synthase kinase-3 beta (p-GSK-3β) and B-cell lymphoma-2 (Bcl-2) and decreased the release of mitochondrial cytochrome c and cleaved caspase-3/9 levels. Therefore, NaHS administration prior to hepatic I/R ameliorates mitochondrial and hepatocellular damage through the inhibition of MPTP opening and the activation of Akt-GSK-3β signaling. Furthermore, this study provides experimental evidence for the clinical use of H2S to reduce liver damage after perioperative I/R injury.

Sodium hydrosulphide against renal ischemia/reperfusion and the possible contribution of nitric oxide in adult male Albino rats

“…For many years, H 2 S was considered a toxic agent that causes 85% mortality at high concentrations. Recently, H 2 S has been recognized as being the third inorganic gaseous mediator and can thus infl uence various cellular processes (8).…”

“…Together, these molecules play a major role in regulating numerous vital biological functions in mammals (7). H 2 S is produced by cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-mercapto-pyruvate-sulfur-transferase (3MST) in mammalian cells (8). H 2 S is abundantly produced in the kidney and liver (9).…”

“…In the liver, the underlying mechanisms of the protection appear to includesuppression of the oxidative stress via antioxidant activities, reduction of the infl ammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and reduction ofhepatocyte apoptosis (8).…”

Decreased Cystathionine-γ-lyase (CSE) Activity in Livers of Type 1 Diabetic Rats and Peripheral Blood Mononuclear Cells (PBMC) of Type 1 Diabetic Patients

“…These studies suggest that H 2 S potentially regulates the cellular redox balance necessary for the inhibition of oxidative stress and cytoprotection. Supplementation of animals with exogenous forms of H 2 S have demonstrated very robust protection of various organs after ischemia-reperfusion injury, stroke, inflammatory disorders, and models of ischemia-induced angiogenesis (6 -9), atherosclerosis (10), retinopathy (11), hepatic injury (12), and renal dysfunction (13). The molecule is endogenously synthesized from L-cysteine via the action of mainly two enzymes, cystathionine-␥-lyase (CSE) 2 and cystathionine-␤-synthase (CBS) (6).…”

Effectiveness of a single versus repeated administration of trimetazidine in the protection against warm ischemia/reperfusion injury of rat liver

“…It has been reported that it limits intracellular acidosis, reduces sodium and calcium accumulation into cells (4), and decreases cytolysis and membrane injury caused by oxygen free radicals (5,6). In addition, TMZ conserves mitochondrial function and energy metabolism (7).…”