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2018 ; 7
(4
): ä Nephropedia Template TP
gab.com Text
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Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits
Experimental Atherosclerosis
#MMPMID29437605
Wen G
; An W
; Chen J
; Maguire EM
; Chen Q
; Yang F
; Pearce SWA
; Kyriakides M
; Zhang L
; Ye S
; Nourshargh S
; Xiao Q
J Am Heart Assoc
2018[Feb]; 7
(4
): ä PMID29437605
show ga
BACKGROUND: To investigate whether neutrophil elastase (NE) plays a causal role
in atherosclerosis, and the molecular mechanisms involved. METHODS AND RESULTS:
NE genetic-deficient mice (Apolipoprotein E(-/-)/NE(-/-) mice), bone marrow
transplantation, and a specific NE inhibitor (GW311616A) were employed in this
study to establish the causal role of NE in atherosclerosis. Aortic expression of
NE mRNA and plasma NE activity was significantly increased in high-fat diet
(HFD)-fed wild-type (WT) (Apolipoprotein E(-/-)) mice but, as expected, not in
NE-deficient mice. Selective NE knockout markedly reduced HFD-induced
atherosclerosis and significantly increased indicators of atherosclerotic plaque
stability. While plasma lipid profiles were not affected by NE deficiency,
decreased levels of circulating proinflammatory cytokines and inflammatory
monocytes (Ly6C(hi)/CD11b(+)) were observed in NE-deficient mice fed with an HFD
for 12 weeks as compared with WT. Bone marrow reconstitution of WT mice with
NE(-/-) bone marrow cells significantly reduced HFD-induced atherosclerosis,
while bone marrow reconstitution of NE(-/-) mice with WT bone marrow cells
restored the pathological features of atherosclerotic plaques induced by HFD in
NE-deficient mice. In line with these findings, pharmacological inhibition of NE
in WT mice through oral administration of NE inhibitor GW311616A also
significantly reduced atherosclerosis. Mechanistically, we demonstrated that NE
promotes foam cell formation by increasing ATP-binding cassette transporter ABCA1
protein degradation and inhibiting macrophage cholesterol efflux. CONCLUSIONS: We
outlined a pathogenic role for NE in foam cell formation and atherosclerosis
development. Consequently, inhibition of NE may represent a potential therapeutic
approach to treating cardiovascular disease.
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