Hepatic Ischemia-Reperfusion Impairs Blood-Brain Barrier Partly Due to Release of Arginase From Injured Liver

Abstract

Aim: Hepatic ischemia-reperfusion (HIR) induces remote organs injury, including the brain. The homeostasis of the brain is maintained by the blood-brain barrier (BBB); thus, we aimed to investigate whether HIR impaired BBB and attempted to elucidate its underlying mechanism.Methods: Cell viability of human cerebral microvascular endothelial cells (hCMEC/D3) was measured following 24 h incubation with a serum of HIR rat undergoing 1 h ischemia and 4 h reperfusion, liver homogenate, or lysate of primary hepatocytes of the rat. The liver homogenate was precipitated using (NH4)2SO4 followed by separation on three columns and electrophoresis to identify the toxic molecule. Cell activity, apoptosis, proliferation, cell cycle, and expressions of proteins related to cell cycle were measured in hCMEC/D3 cells incubated with identified toxic molecules. HIR rats undergoing 1 h ischemia and 24 h reperfusion were developed to determine the release of an identified toxic molecule. BBB function was indexed as permeability to fluorescein and brain water. Endothelial cell proliferation and expressions of proteins related to the cell cycle in cerebral microvessels were measured by immunofluorescence and western blot.Results: Toxic molecule to BBB in the liver was identified to be arginase. Arginase inhibitor nor-NOHA efficiently attenuated hCMEC/D3 damage caused by liver homogenate and serum of HIR rats. Both arginase and serum of HIR rats significantly lowered arginine (Arg) in the culture medium. Arg addition efficiently attenuated the impairment of hCMEC/D3 caused by arginase or Arg deficiency, demonstrating that arginase impaired hCMEC/D3 via depriving Arg. Both arginase and Arg deficiency damaged hCMEC/D3 cells by inhibiting cell proliferation, retarding the cell cycle to G1 phase, and downregulating expressions of cyclin A, cyclin D, CDK2, and CDK4. HIR notably increased plasma arginase activity and lowered Arg level, increased the BBB permeability accompanied with enhanced brain water, and decreased the proliferative cells (marked by Ki67) in cerebral microvessels (marked by CD31) and protein expressions of cyclin A, cyclin D, CDK2 and CDK4 in isolated brain microvessels. Oral supplement of Arg remarkably attenuated these HIR-induced alterations.Conclusion: HIR leads to substantial release of arginase from the injured liver and then deprives systemic Arg. The Arg deficiency further impairs BBB via inhibiting the proliferation of brain microvascular endothelial cells by cell cycle arrest.

Transcranial Doppler Ultrasound and Transesophageal Echocardiography for Intraoperative Diagnosis and Monitoring of Patent Foramen Ovale in Non-Cardiac Surgery

“…However, many confounding factors should be considered in the next studies to establish a correlation between PFO and neurological and respiratory outcomes: the different surgical interventions, the hemodynamic instability, the perioperative metabolic derangement such as pre-operative encephalopathy, chronic obstructive pulmonary disease, end-stage liver disease MELD-Na score, acute kidney injury (AKI), perioperative infections and hemodynamic instability, ischaemia-reperfusion injury (PRS), and levels of ammonium, glucose and sodium [26,[31][32][33][34][35][36][37][38][39][40][41][42]. In this case series, the main variables that could interfere with the development of neurological complications were evaluated (see Table 2).…”

Bile duct ligation elevates 5-HT levels in cerebral cortex of rats partly due to impairment of brain UGT1A6 expression and activity via ammonia accumulation

“…All antibodies used in the immunofluorescence assays are listed in Table S2 . Immunofluorescence assays of the brain sections were conducted as we previously described [ 38 ]. Briefly, after deparaffinization, paraffin-embedded sections of rat brains were incubated with normal goat serum and mixed with primary antibodies against mouse anti-UGT1A6 and rat anti-GFAP.…”

Arginase: shedding light on the mechanisms and opportunities in cardiovascular diseases

“…On the other side, arginase’s enzymatic activity results in the consumption of L-arginine which is required in some types of cells, resulting in delayed growth and even death. Hepatic ischemia-reperfusion leads to substantial release of arginase and then deprives systemic L-arginine, which further inhibits the proliferation of brain microvascular endothelial cells by cell cycle arrest [ 88 ]. Overall, arginase is engaged in the regulation of cell proliferation and has significant implications for angiogenesis, vascular remodeling as well as cardiovascular functions.…”