Anti-PCSK9 antibodies inhibit pro-atherogenic mechanisms in APOE*3Leiden.CETP mice.
Susanne SchusterSandra RubilMatthias EndresHans M G PrincenJes-Niels BoeckelKarsten WinterChristian WernerUlrich LaufsPublished in: Scientific reports (2019)
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.
Keyphrases
- low density lipoprotein
- high fat diet
- endothelial cells
- cardiovascular events
- high fat diet induced
- peripheral blood
- induced apoptosis
- insulin resistance
- adipose tissue
- coronary artery disease
- oxidative stress
- cognitive decline
- cardiovascular disease
- cell cycle arrest
- signaling pathway
- anti inflammatory
- pulmonary hypertension
- left ventricular
- aortic valve
- metabolic syndrome
- poor prognosis
- endoplasmic reticulum stress
- multiple myeloma
- skeletal muscle
- pulmonary arterial hypertension