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Journal of Lipid Research, Vol. 49, 2338-2346, November 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Cannabinoid (CB2) receptor deficiency reduces the susceptibility of macrophages to oxidized LDL/oxysterol-induced apoptosis^*

Natalie E. Freeman-Anderson^1,*, Theresa G. Pickle^*, Courtney D. Netherland^*, Alicia Bales^*, Nancy E. Buckley and Douglas P. Thewke^1,2,*

^* Department of Biochemistry and Molecular Biology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN
the Department of Biological Sciences, California State Polytechnic University, Pomona, CA
¹ N. E. Freeman-Anderson and D. P. Thewke contributed equally to this work.

^* This work was supported by the National Institutes of Health (NIH) grant HL085137 (D.P.T).

Published, JLR Papers in Press, July 9, 2008.

² To whom correspondence should be addressed. e-mail: Thewke{at}etsu.edu

Macrophage apoptosis is an important process in the pathophysiology of atherosclerosis. Oxidized low-density lipoproteins (OxLDL) are a major component of lesions and potently induce macrophage apoptosis. Cannabinoid receptor 2 (CB2), the predominant macrophage cannabinoid receptor, modulates several macrophage processes associated with ongoing atherosclerosis; however, the role of CB2 in macrophage apoptosis is unknown. To determine if CB2 influences a macrophage apoptotic pathway relevant to atherosclerosis, we examined the effect of CB2 deficiency on OxLDL-induced macrophage apoptosis. In situ terminal transferase-mediated dUTP nick end labeling (TUNEL) analysis of resident peritoneal macrophages detected significantly fewer apoptotic CB2^–/– macrophages than CB2^+/+ macrophages after incubation with OxLDL (27.9 ± 4.7% vs. 61.9 ± 8.5%, P < 0.001) or 7-ketocholesterol (7KC) (18.9 ± 10.5% vs. 54.1 ± 6.9%, P < 0.001), an oxysterol component of OxLDL. Caspase-3 activity; proteolytic conversion of procaspase-3; and cleavage of a caspase-3 substrate, PARP, were also diminished in 7KC-treated CB2^–/– macrophages. Furthermore, the deactivation of the prosurvival kinase, Akt, in response to 7KC was impaired in CB2^–/– macrophages. These results suggest that CB2 expression increases the susceptibility of macrophages to OxLDL-induced apoptosis, in part, by modulating the effect of oxysterols on the Akt survival pathway and that CB2 may influence atherosclerosis by modulating lesional macrophage apoptosis.

Supplementary key words 7-ketocholesterol • Akt • atherosclerosis • caspase-3

Abbreviations: ACAT, acyl-coenzyme A:cholesterol transferase; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; cPLA₂, cytosolic phospholipase A₂; mOxLDL, minimally oxidized LDL; MPMs, mouse peritoneal macrophages; OxLDL, oxidized low density lipoproteins; PARP, poly-ADP ribose polymerase; THC, ⁹-tetrahydrocannabinol; TUNEL, terminal transferase-mediated dUTP nick end labeling; 7KC, 7-ketocholesterol

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