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120 Genetic and pharmacologic inhibition of the neutrophil elastase inhibits experimental atherosclerosis
  1. Weiwei an,
  2. Guanmei Wen
  1. QMUL, Clinical Pharmacology, Charterhouse Square, London, UK


Background To investigate if neutrophil elastase (NE) plays a causal role in atherosclerosis, and the molecular mechanisms involved.

Methods and results NE genetic deficient mice (ApoE-/-/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) (ApoE-/-) 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. Whilst plasma lipid profiles were not affected by NE-deficiency, decreased levels of circulating pro-inflammatory cytokines and inflammatory monocytes (Ly6Chi/CD11b+) were observed in NE-deficient mice fed with HFD for 12 weeks as compared to 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 have 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.

  • Neutrophil elastase
  • Atherosclerosis
  • Foam cell

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