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

Xu, Jin, MD1,2; Xue, Zhengze, MD1,3; Zhang, Cheng, MD1,3; Liu, Yuan, MD1,4; Busuttil, Ronald W., MD1; Zhang, Jiamin, MD5; Kupiec-Weglinski, Jerzy W., MD1; Ji, Haofeng, MD1

doi: 10.1097/TP.0000000000002614
Original Basic Science—Liver
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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 0.5 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).

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.

1 Division of Liver and Pancreas Transplantation, Department of Surgery, Dumont-UCLA Transplant Center, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.

2 Department of Pancreatic Surgery, Shengjing Hospital, China Medical University, Shenyang, China.

3 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

4 Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.

5 Department of Surgery, People’s Hospital of Jinhua, Jinhua, Zhejiang, China.

Received 8 November 2018. Revision received 30 November 2018.

Accepted 16 December 2018.

J.X., Z.X., and C.Z. contributed equally to this work.

J.X., Z.X., and C.Z. participated in the performance of the research and data analysis. Y.L. participated in the performance of the research. R.W.B. and J.W.K.W. participated in article revision. J.Z. and H.J. participated in the research design, discussion, and article writing.

The authors declare no conflicts of interest.

H.J. was supported by NIH Grant R21 (AI122155 and AI138165). J.W.K.W. was supported by PO1 (AI120944), RO1 (DK107533, DK102110, and DK062357), and The Dumont Research Foundation.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Haofeng Ji, MD, Division of Liver and Pancreas Transplantation, Department of Surgery, Dumont-UCLA Transplant Center, David Geffen School of Medicine at University of California-Los Angeles, 77–120 CHS, 10833 Le Conte Ave, Los Angeles, CA 90095. (hji@mednet.ucla.edu);

Jiamin Zhang, MD, 228 Xinhua St, Jinhua, Zhejiang 321000, China. (zjm0323001@126.com).

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