Abstract
LDL-cholesterol (LDL-C) is a causal pathogenic factor in atherosclerosis. Monoclonal anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) neutralizing antibodies are novel potent LDL-lowering drugs which reduce cardiovascular events. To characterize their effect on atherogenesis, APOE*3Leiden.CETP mice were fed a high cholesterol/high fat diet (WTD) or normal chow (NC) for 18 weeks. Mice on WTD were injected with the human anti-PCSK9 antibody mAb1 (PL-45134, 10 mg*kg−1 s.c.) or 0.9% saline every 10 days. PCSK9 inhibition decreased total cholesterol in serum of APOE*3Leiden.CETP mice and prevented the development of atherosclerosis. The plaque area in the aortic root was reduced by half and macrophage infiltration determined by Ly6c and Mac-3 staining was ameliorated. PCSK9 inhibition decreased markers of inflammation in mononuclear cells (Il-6, Tnfa mRNA), and in serum (CXCL-1,-10,-13; complement factor C5a) compared to control WTD fed animals. The number of circulating Sca-1/VEGF-R2 positive endothelial progenitor cells of the peripheral blood and spleen-derived diLDL/lectin double positive circulating angiogenic cells was increased. To conclude, the PCSK9-mediated anti-atherosclerotic effect involves the upregulation of pro-regeneratory endothelial progenitor cells, a reduction of inflammation and change of plaque composition.
Highlights
Low-density lipoprotein cholesterol (LDL-C) causally contributes to the pathogenesis of atherosclerosis
We aimed to characterize the vascular effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in APOE*3Leiden.cholesteryl ester transfer protein (CETP) mice, a mouse model for familial dysbetalipoproteinemia with human-like lipoprotein metabolism[30,31,32], on atherosclerosis development, inflammation and endothelial progenitor cells (EPC) and circulating angiogenic cells (CAC) number
The plaque area was reduced by half compared to saline-treated mice (Fig. 1B,C)
Summary
Low-density lipoprotein cholesterol (LDL-C) causally contributes to the pathogenesis of atherosclerosis. Atherosclerosis is characterized by chronic inflammation of the arterial wall beginning with the retention of Apolipoprotein B–containing lipoproteins within the subendothelial intima of arteries. This leads to the activation of endothelial cells followed by leukocyte adhesion and migration; foam cell formation and activation of vascular smooth muscle cells leading to increased production of extracellular matrix[16]. We aimed to characterize the vascular effects of PCSK9 inhibition in APOE*3Leiden.cholesteryl ester transfer protein (CETP) mice, a mouse model for familial dysbetalipoproteinemia with human-like lipoprotein metabolism[30,31,32], on atherosclerosis development, inflammation and EPC and CAC number
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