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

Background: 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. Methods: This study evaluated the modulation and therapeutic potential of CDK2 inhibition in a mouse model of partial liver warm IRI. Results: Liver IR triggered intrinsic CDK2 expression, peaking by 0.5h of reperfusion, and maintaining a high level throughout 1h-24h. Roscovitine, a specific CDK2 inhibitor, prevented liver IR mediated damage with abolished serum ALT levels and reserved liver pathology. CDK2 inhibition mediated liver protection was accompanied by decreased macrophage/neutrophil infiltration, diminished hepatocyte apoptosis, abolished TLR4 signaling and downstream gene inductions (CXCL-10, TNF-a, IL-1β and IL-6), yet augmented IL-10 expression. In vitro, CDK2 inhibition by Roscovitine suppressed macrophage TLR4 activation, and further depressed downstream inflammatory signaling (MyD88, IRF3, p38, JNK and ERK). Conclusions: 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. * These authors contributed equally to this work Disclosure: The authors declare no conflicts of interest. Funding: NIH Grant R21 AI122155 and AI138165 (HJ). PO1 AI120944, RO1 DK107533, DK102110, and DK062357 (JWKW). The Dumont Research Foundation. Correspondence Information: Haofeng Ji, MD. Dumont-UCLA Transplant Center, 77-120 CHS, 10833 Le Conte Ave, Los Angeles, CA 90095. Phone: (310) 206-0328; Fax: (310) 267-2367; Email: hji@mednet.ucla.edu. Jiamin Zhang, MD. 228 Xinhua st, Jinhua, Zhejiang, China, 321000. Email: zjm0323001@126.com. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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