Introduction β-amyloid (Aβ) is produced via the cleavage of amyloid precursor protein β-secretase (BACE1), resulting in the formation of amyloid plaques, a hallmark pathology of Alzheimer’s disease (AD). AD, type 2 diabetes, obesity and cardiovascular disease appear intimately linked with endothelial dysfunction, inflammation, insulin resistance and elevated AÃƒÅ¸ levels all common features. Impaired endothelial function is represented by impaired endothelium-dependent, nitric-oxide (NO)-mediated relaxation. Tight regulation of vasoactive compounds such as endothelin-1 (ET-1) and NO are required to maintain vascular tine. An imbalance, resulting in increased ET-1 and reduced NO levels promotes vascular stiffening and consequently diseases such as diabetic retinopathy, nephropathy and atherosclerosis. Diseases caused by an increased atherosclerosis burden including coronary heart disease and stroke are major causes of death in obese and diabetic populations.
Aims Determine (1) whether enhanced Aβ levels are sufficient to induce vascular dysfunction and (2) if reducing Aβ production can reverse diet-induced vascular dysfunction.
Methods Measurements of vascular function was determined in vivo by the vascular response to Acetylcholine (endothelial dependent or Sodium Nitroprusside (endothelial independent) using laser Doppler imaging in two studies; (i) Wild-type (C57BL/6) mice fed a regular chow diet were infused with murine αβ42 or scrambled peptide (ScP; 3.36μg/kg) in aCSF for 6 weeks or (ii) a BACE1 inhibitor (M-3; 10mg/kg) or vehicle (DMSO/PBS) into diet-induced obese (DIO) C57BL/6 mice. Western blotting and ELISAs were used to measure vascular NO signalling and Aβ production.
Results Circulating levels of Aβ42, not the more prevalent Aβ40 isoform, are increased in both high fat fed mice and obese/diabetic human patients. Infusion of M-3 into DIO mice rescued endothelial dependent reactivity (M-3 27.1 5.9, vehicle 1.3 2.9; P<0.01). In contrast, infusion of Aβ42 promoted impaired vascular responses Aβ 14.13.7, ScP 38.33.2; P<0.001) on regular chow with no change in body weight. In line with our hypothesis infusion of Aβ42 increases the ET-1/NO ratio (ScP 1.12β 0.05, Aβ42 5.35 0.89; P<0.001), while DIO mice treated with a BACE1 inhibitor, thus with reduced plasma Aβ42 levels, have a low ET-1/NO ratio (M-3 1.29 0.9, DIO 4.6 1.3; P<0.05).
Conclusions We suggest that amyloid processing has a role in normal vascular function with aberrant processing leading to endothelial dysfunction and hypertension. Here we show that pharmacological inhibition of BACE1 can reverse diet-induced endothelial dysfunction, via modulation of plasma Aβ42 levels, as infusion of Aβ42 can promote the dysfunction independent of a high fat diet.
- Endothelial dysfunction
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