Abstract
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.
Highlights
Macrophage apoptosis is an important process in the pathophysiology of atherosclerosis
We performed transferase-mediated dUTP nick end labeling (TUNEL) analysis of CB22/2 and CB21/1 mouse peritoneal macrophages (MPMs) incubated for 16 h with increasing amounts of Oxidized lowdensity lipoproteins (OxLDL) to examine the effect of Cannabinoid receptor 2 (CB2) deficiency in macrophages on OxLDL-induced apoptosis (Fig. 1C)
To determine if CB2 influences the apoptotic response of macrophages to OxLDL/oxysterols, we examined apoptosis in CB22/2 and CB21/1 resident peritoneal macrophages following exposure to OxLDL or 7KC
Summary
Macrophage apoptosis is an important process in the pathophysiology of atherosclerosis. Oxidized lowdensity lipoproteins (OxLDL) are a major component of lesions and potently induce macrophage apoptosis. The deactivation of the prosurvival kinase, Akt, in response to 7KC was impaired in CB22/2 macrophages These results suggest that CB2 expression increases the susceptibility of macrophages to OxLDLinduced 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.—Freeman-Anderson, N. Oxidized low-density lipoproteins (OxLDL) is the most widely studied modified LDL It is present in circulating plasma and atherosclerotic lesions [7, 8], and is a potent inducer of apoptosis in cultured macrophages as well as other vascular cell types [9,10,11,12].
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