Protective effect of apelin preconditioning in a rat model of hepatic ischemia reperfusion injury; possible interaction between the apelin/APJ system, Ang II/AT1R system and eNOS

Abstract

Introduction: Hepatic ischemic reperfusion injury occurs in multiple clinical settings. Novel potential protective agents are still needed to attenuate this injury. Apelin preconditioning protects against ischemic reperfusion injury in different organs. However, the protective mechanism of apelin on hepatic ischemic reperfusion injury is not yet clear. Aim: Evaluate the effect of apelin-13 preconditioning on hepatic ischemic reperfusion injury and clarify possible interactions between apelinergic, renin-angiotensin systems and endothelial nitric oxide synthase. Methods: In total, 60 rats were assigned to four groups: control sham-operated, ischemic reperfusion, apelin-treated ischemic reperfusion and apelin þ N-nitro-L-arginine methyl ester-treated ischemic reperfusion. Apelin 2 mg/kg/day and N-nitro-L-arginine methyl ester 10 mg/kg/day were injected intraperitoneally daily for 3 days and 2 weeks respectively before hepatic ischemic reperfusion. Serum aminotransferase, aspartate aminotransferase, hepatic malondialdehyde, apelin, gene expression of caspase-3, endothelial nitric oxide synthase and angiotensin type 1 receptor and liver histopathology were compared between groups. Results: Apelin significantly reduced serum aminotransferase, aspartate aminotransferase, hepatic malondialdehyde, caspase-3 and angiotensin type 1 receptor expression, whereas hepatic apelin and endothelial nitric oxide synthase expression were significantly increased with improved hepatic histopathology. N-nitro-L-arginine methyl ester co-administration partially reversed this hepatoprotective effect. Conclusion: Apelin-13 reduced hepatic ischemic reperfusion injury. This protection could be related to the suppression of hepatic angiotensin type 1 receptor expression and elevation of hepatic apelin level and endothelial nitric oxide synthase expression, which counteracts the pathologic effects of Ang II/angiotensin type 1 receptor. An interaction exists between apelinergic, renin-angiotensin systems and endothelial nitric oxide synthase in hepatic ischemic reperfusion pathophysiology.

Role of the PI3K/Akt signaling pathway in liver ischemia reperfusion injury: a narrative review

“…The activated PI3K/ Akt signaling pathway promotes the generation of heme oxygenase-1 (HO-1) by upregulating the expression of Nrf2, thus alleviating oxidative stress injury during LIRI (43)(44)(45)(46)(47). In addition, activation of PI3K/Akt pathway can activate endothelial nitric oxide synthase (eNOS) in vascular endothelial cells, increase the formation of nitric oxide (NO), and further improve LIRI (48)(49)(50).…”

Adipokines, Myokines, and Cardiokines: The Role of Nutritional Interventions

“…Data reported in literature reveal that apelinergic signaling plays a crucial role in decreased ROS production [101] and protection the heart against ischemia/reperfusion injury activating Akt, ERK/MAPK, and eNOS pathways [102,103].…”

Apelin-13 Protects Dopaminergic Neurons against Rotenone—Induced Neurotoxicity through the AMPK/mTOR/ULK-1 Mediated Autophagy Activation

“…Studies have shown that apelin-13 is able to penetrate the blood-brain barrier via an unsaturated mechanism, which indicates that it is feasible to transport to the central nervous system pharmacologically through peripheral pathways [33]. Apelin-13 is a neuropeptide which is capable of protecting against neuronal apoptosis and excitotoxicity in vitro, and is associated with neuronal survival in vivo following cerebral ischemia or ischemia/reperfusion injury, amyotrophic lateral sclerosis (ALS), and seizure [34][35][36]. In addition, apelin-13 has an attenuating effect on the expression of pro-inflammatory cytokines, and inhibits microglia, astrocytes, and other inflammatory cells [37,38].…”