Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury

Sándor Bátkai, Douglas Osei-Hyiaman, Hao Pan, Osama El-Assal, Mohanraj Rajesh, Partha Mukhopadhyay, Feng Hong, Judith Harvey-White, Anjum Jafri, György Haskó, John W. Huffman, Bin Gao, George Kunos, Pál Pacher

Research output: Contribution to journalArticlepeer-review

217 Citations (Scopus)

Abstract

Hepatic ischemia-reperfusion (I/R) injury continues to be a fatal complication that can follow liver surgery or transplantation. We have investigated the involvement of the endocannabinoid system in hepatic I/R injury using an in vivo mouse model. Here we report that I/R triggers several-fold increases in the hepatic levels of the endocannabinoids anandamide and 2-arachidonoylglycerol, which originate from hepatocytes, Kupffer, and endothelial cells. The I/R-induced increased tissue endocannabinoid levels positively correlate with the degree of hepatic damage and serum TNF-α, MIP-1α, and MIP-2 levels. Furthermore, a brief exposure of hepatocytes to various oxidants (H2O2 and peroxynitrite) or inflammatory stimuli (endotoxin and TNF-α) also increases endocannabinoid levels. Activation of CB2 cannabinoid receptors by JWH133 protects against I/R damage by decreasing inflammatory cell infiltration, tissue and serum TNF-α, MIP-1α and MIP-2 levels, tissue lipid peroxidation, and expression of adhesion molecule ICAM-1 in vivo. JWH133 also attenuates the TNF-α-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and the adhesion of human neutrophils to HLSECs in vitro. Consistent with the protective role of CB2 receptor activation, CB2 -/- mice develop increased I/R-induced tissue damage and proinflammatory phenotype. These findings suggest that oxidative/nitrosative stress and inflammatory stimuli may trigger endocannabinoid production, and indicate that targeting CB2 cannabinoid receptors may represent a novel protective strategy against I/R injury. We also demonstrate that CB2 -/- mice have a normal hemodynamic profile.

Original languageEnglish
Pages (from-to)1788-1800
Number of pages13
JournalFASEB Journal
Volume21
Issue number8
DOIs
Publication statusPublished - Jun 2007
Externally publishedYes

Keywords

  • 2-arachidonoylglycerol
  • Anandamide
  • Endocannabinoids
  • Oxidative stress
  • Peroxynitrite

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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