Macrophages from alpha 7 nicotinic acetylcholine receptor knockout mice demonstrate increased cholesterol accumulation and decreased cellular paraoxonase expression: a possible link between the nervous system and atherosclerosis development.
OBJECTIVE
The parasympathetic nervous system regulates inflammation in peripheral tissues through a pathway termed the "cholinergic anti-inflammatory reflex" (CAIR). Mice deficient in the alpha 7 nicotinic acetylcholine receptor (alpha7(-/-)) have an impaired CAIR due to decreased signaling through this pathway. The purpose of this study was to determine if the increased inflammation in alpha7(-/-) mice is associated with enhanced serum and macrophage atherogenicity.


METHODS
We measured serum markers of inflammation and oxidative stress, and macrophage atherogenicity in mouse peritoneal macrophages harvested from alpha7(-/-) mice on the background of C57BL/6 mice, as well as on the background of the atherosclerotic Apolipoprotein E-deficient (ApoE(-/-)) mice.


RESULTS
alpha7-Deficiency had no significant effects on serum cholesterol, or on markers of serum oxidative stress (TBARS and paraoxonase1 activities). However, alpha7-deficiency significantly increased serum CRP and IL-6 (p<0.05) levels in atherosclerotic mice, confirming an anti-inflammatory role for the alpha7 receptor. Macrophage cholesterol mass was increased by 25% in both normal and atherosclerotic mice in the absence of the alpha7 receptor (p<0.05). This was accompanied by conditional increases in oxidized LDL uptake and in macrophage total peroxide levels. Furthermore, alpha7-deficiency reduced macrophage paraoxonase2 mRNA and activity by 50-100% in normal and atherosclerotic mice (p<0.05 for each), indicating a reduction in macrophage anti-oxidant capacity in the alpha7(-/-) mice.


CONCLUSIONS
The above results suggest an anti-atherogenic role for the macrophage alpha7nAchr, through a mechanism that involves attenuated macrophage oxidative stress and decreased uptake of oxidized LDL.
Department of Kinesiology and Community Health, University of Illinois, Urbana, IL 61801, USA. kwilund@illinois.edu
Kenneth R
KR
Wilund
Mira
M
Rosenblat
Hae Ryong
HR
Chung
Nina
N
Volkova
Marielle
M
Kaplan
Jeffrey A
JA
Woods
Michael
M
Aviram
D000818:Animals; D043303:Aryldialkylphosphatase / Q000096:biosynthesis*; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D007249:Inflammation / Q000150:complications / Q000201:enzymology / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D010275:Parasympathetic Nervous System / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579166:Chrna7 protein, mouse; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D002784:Cholesterol; D043303:Aryldialkylphosphatase