Submitted on February 28, 2008
Revised on July 8, 2008
Accepted on July 8, 2008
Cannabinoid (CB2) receptor deficiency reduces the susceptibility of macrophages to oxidized LDL/oxysterol-induced apoptosis
Natalie E. Freeman-Anderson, Theresa G. Pickle, Courtney D. Netherland, Alicia Bales, Nancy E. Buckley, and Douglas P. Thewke
Biochemistry & Molecular Biology, East Tennessee State Univsersity, Johnson City, TN 37614
Corresponding Author: 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. 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 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 pro-caspase-3, and cleavage of a caspase-3 substrate, PARP, were also diminished in 7KC-treated CB2-/- macrophages. Furthermore, the deactivation of the pro-survival 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.
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