Inhibition of Cyclin-dependent Kinase 2 Signaling Prevents Liver Ischemia and Reperfusion Injury.

Abstract

Liver ischemia and reperfusion injury (IRI) is a major complication of liver transplant, hepatectomy, and hemorrhagic shock. The cyclin-dependent kinase 2 (CDK2) acts as a pivotal regulator of cell cycle and proliferation. This study evaluated the modulation and therapeutic potential of CDK2 inhibition in a mouse model of partial liver warm IRI. Liver IR-triggered intrinsic CDK2 expression, peaking by 0.5 hour of reperfusion and maintaining a high-level throughout 1 to 24 hours. Roscovitine, a specific CDK2 inhibitor, prevented liver IR-mediated damage with abolished serum alanine aminotransferase levels and reserved liver pathology. CDK2 inhibition-mediated liver protection was accompanied by decreased macrophage/neutrophil infiltration, diminished hepatocyte apoptosis, abolished toll like receptor 4 signaling and downstream gene inductions (C-X-C motif ligand-10, Tumor necrosis factor-α, interleukin-1β, and interleukin-6), yet augmented interleukin-10 expression. In vitro, CDK2 inhibition by Roscovitine suppressed macrophage TLR4 activation and further depressed downstream inflammatory signaling (myeloid differentiation factor 88, interferon regulatory transcription factor 3, p38, c-Jun N-terminal kinase, and extracellular-regulated kinase). Our novel findings revealed the critical role of CDK2 in hepatic cytoprotection and homeostasis against liver IRI. As CDK2 inhibition regulated local immune response and prevented hepatocyte death, this study provided the evidence for new treatment approaches to combat IRI in liver transplant.