Molecular mechanisms of liver preconditioning

Figure 1 Signalling pathways involved in the development of ischemic preconditioning in rat hepatocytes. Adenosine triphosphate (ATP), adenosine and nitric oxide (NO) act as inductors of hepatocyte preconditioning by modulating a network of constitutive and newly synthesized signal mediators. Some of these mediators play a common central role in hepatocyte cytoprotection. p38 MAP kinase (p38 MAPK) is a mediator of the cytoprotective effects of all three preconditioning stimuli. Phosphatidylinositol 3-kinase (PI3K) mediates both adenosine and NO early resistance to hypoxia. PI3K together with protein kinase C (PKC) δ and ε, also induces hepatocyte late resistance to hypoxia contributing to the normoxic activation of hypoxia-inducible factor 1 (HIF-1). Diacylglycerol kinase theta (DGKθ) and the phosphatase tensin-homologues-deleted from chromosome 10 (PTEN) which metabolize diacyglycerol and phosphatidylinositol, respectively, are inhibited during preconditioning to sustain activation of the diacylglycerol (DAG)-dependent PKC δ and ε and the PI3K-dependent signals. See text and Refs[21,25,27,28,32,35,37,43]. P2YR: Purinergic P2Y receptors; A2aR: Adenosine 2A receptors; S-CG: Soluble guanylate cyclase; cGMP: Cyclic guanosine monophosphate; cGK: cGMP-dependent kinase; AC: Adenylate cyclase; cAMP: Cyclic adenosine monophosphate; PIP3: Phosphatidylinositol-3-phosphate; PKA: Protein kinase A; CAIX: Carbonic anhydrase IX; PLC: Phospholipase C; PA: Phosphatidic acid.

Figure 2 Na⁺-dependent mechanisms involved in hepatocyte damage by hypoxia and their modulation by ischemic preconditioning. Hypoxia-induced adenosine triphosphate (ATP) depletion causes intracellular acidification, leading to inhibition of Na⁺/K⁺ ATPase and the activation of acid buffering systems (Na⁺/H⁺ exchanger). This leads to an increase in intracellular Na⁺ that precipitates irreversible hepatocyte damage. ATP-dependent signalling through purinergic P2Y receptors prevents Na⁺ accumulation by inhibiting the ERK 1/2-dependent activation of the Na⁺/H⁺ exchanger. Adenosine and nitric oxide (NO) activate the vacuolar proton ATPase that maintains intracellular pH avoiding activation of the Na⁺/H⁺ exchanger. Adenosine also induces the hypoxia-inducible factor 1 (HIF-1) target gene, carbonic anhydrase IX (CAIX), which converts CO₂ into bicarbonate, that once transported into the hepatocytes through the Cl^-/HCO₃^- exchanger, neutralizes the intracellular pH and prevents Na⁺ accumulation. See text and Refs[20,21,25,27,28,43,52,53,58]. P38 MAPK: p38 MAP kinase; PI3-kinase: Phosphatidylinositol 3-kinase; PKC: Protein kinase C.