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, G. Haskó, John W. Huffman, Bin Gao, George Kunos, Pál Pacher

Research output: Contribution to journalArticle

186 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

Fingerprint

cannabinoids
Cannabinoid Receptors
Endocannabinoids
Cannabinoids
ischemia
Reperfusion Injury
Cannabinoid Receptor CB2
Endothelial cells
liver
receptors
Liver
Tissue
hepatocytes
Ischemia
Intercellular Adhesion Molecule-1
endothelial cells
Reperfusion
Endothelial Cells
Adhesion
Chemical activation

Keywords

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

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Bátkai, S., Osei-Hyiaman, D., Pan, H., El-Assal, O., Rajesh, M., Mukhopadhyay, P., ... Pacher, P. (2007). Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. FASEB Journal, 21(8), 1788-1800. https://doi.org/10.1096/fj.06-7451com

Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. / Bátkai, Sándor; Osei-Hyiaman, Douglas; Pan, Hao; El-Assal, Osama; Rajesh, Mohanraj; Mukhopadhyay, Partha; Hong, Feng; Harvey-White, Judith; Jafri, Anjum; Haskó, G.; Huffman, John W.; Gao, Bin; Kunos, George; Pacher, Pál.

In: FASEB Journal, Vol. 21, No. 8, 06.2007, p. 1788-1800.

Research output: Contribution to journalArticle

Bátkai, S, Osei-Hyiaman, D, Pan, H, El-Assal, O, Rajesh, M, Mukhopadhyay, P, Hong, F, Harvey-White, J, Jafri, A, Haskó, G, Huffman, JW, Gao, B, Kunos, G & Pacher, P 2007, 'Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury', FASEB Journal, vol. 21, no. 8, pp. 1788-1800. https://doi.org/10.1096/fj.06-7451com
Bátkai S, Osei-Hyiaman D, Pan H, El-Assal O, Rajesh M, Mukhopadhyay P et al. Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. FASEB Journal. 2007 Jun;21(8):1788-1800. https://doi.org/10.1096/fj.06-7451com
Bátkai, Sándor ; Osei-Hyiaman, Douglas ; Pan, Hao ; El-Assal, Osama ; Rajesh, Mohanraj ; Mukhopadhyay, Partha ; Hong, Feng ; Harvey-White, Judith ; Jafri, Anjum ; Haskó, G. ; Huffman, John W. ; Gao, Bin ; Kunos, George ; Pacher, Pál. / Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. In: FASEB Journal. 2007 ; Vol. 21, No. 8. pp. 1788-1800.
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