In vivo knockdown of nicotinic acetylcholine receptor α1 diminishes aortic atherosclerosis.
OBJECTIVE
Nicotinic acetylcholine receptor α1 (nAChRα1) was recently identified as a functional cell receptor for urokinase, a potent atherogenic molecule. Here, we test the hypothesis that nAChRα1 plays a role in the pathogenesis of atherosclerosis.


METHODS
Apolipoprotein E-deficient mice were initially fed a Western diet for 8 wks. Plasmid DNA encoding scramble RNA (pscr) or siRNA (psir2) for nAChRα1 was injected into the mice (n=16) using an aortic hydrodynamic gene transfer protocol. Four mice from each group were sacrificed 7 days after the DNA injection to confirm the nAChRα1 gene silencing. The remaining mice continued on a Western diet for an additional 16 wks.


RESULTS
The nAChRα1 was up-regulated in aortic atherosclerotic lesions. A 78% knockdown of the nAChRα1 gene resulted in remarkably less severe aortic plaque growth and neovascularization at 16 wks (both P<0.05). In addition, significantly fewer macrophages (60% less) and myofibroblasts (80% less) presented in the atherosclerotic lesion of the psir2-treated mice. The protective mechanisms of the nAChRα1 knockdown may involve up-regulating interferon-γ/Y box protein-1 activity and down-regulating transforming growth factor-β expression.


CONCLUSIONS
The nAChRα1 gene plays a significant role at the artery wall, and reducing its expression decreases aortic plaque development.
Zhang
Guoqiang
G
Division of Nephrology, Seattle Children's Hospital, Department of Pediatrics, University of Washington, Seattle, WA 98105, USA. gqzhang@u.washington.edu
Marshall
Amanda L
AL
Thomas
Alison L
AL
Kernan
Kelly A
KA
Su
Yanyuan
Y
LeBoeuf
Renee C
RC
Dong
Xiu Rong
XR
Tchao
B N Angela
BN
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001018:Aortic Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D020868:Gene Silencing; D007371:Interferon-gamma / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D015854:Up-Regulation
D000199:Actins; D007371:Interferon-gamma; D011978:Receptors, Nicotinic; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C555576:CHRNA1 protein, mouse; C541744:Ybx1 protein, mouse
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