Metabolic disease (Type 2 diabetes and obesity), neurodegeneration and auto-immune diseases are all characterised by chronic inflammation. We are interested in the vascular consequences of inflammation by understanding the molecular mechanisms involved. Vascular inflammation is a complex immune response occurring in blood vessels, characterised by endothelial dysfunction, activation of immune cells and perivascular adipose tissue and the release of proinflammatory chemokines and cytokines. Damaged blood vessels increased risk of developing cardiovascular diseases which is a precursor to vascular complications including atherosclerosis, heat attack and stroke.
The protease β-site APP-cleaving enzyme 1 (BACE1) is associated with Alzheimer’s disease development, via the production of β-amyloid peptides. However, our work using proteomics and RNAseq analysis has shown increased BACE1 activity drives endothelial dysfunction. Furthermore, we have identified genetic associations with hyperlipidaemia and hypertension. Here we explore the hypothesis that BACE1 could be a novel drug target for vascular disease.
Results: BACE1 is highly expressed in endothelial and smooth muscle cells in human atherosclerotic lesions. With elevated expression occurring in the early phases of lesion development.
Four-week treatment of a BACE1 inhibitor (Merck-3) in Western diet fed ApoE KO mice reduced atherosclerotic plaque load by 50% both in the whole aorta and aortic root (P<0.05). Furthermore, BACE1 inhibition lowered vascular inflammation (P< 0.01), serum triglyceride (P< 0.01) and LDL cholesterol (P< 0.05) levels and reduced hypertension (P< 0.05) compared to vehicle controls. Mechanistically, BACE1 inhibition restores endothelial cells and vascular function.
Conclusions: Taken together our data demonstrate that elevated BACE1 activity is a driving factor of atherosclerotic lesion development via induction of endothelial dysfunction. Thus, targeting this with available BACE1 inhibitors could be a novel therapy for atherosclerosis and vascular disease. These findings have the potential to have wide ranging impact as the interrelation of blood vessels, inflammation and immunity is a fundamental physiological process while also underlying several diseases, ranging from infections to autoimmune diseases, metabolic syndrome, dementia.