Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction.

ABSTRACT: Diabetes, obesity, and Alzheimer's disease (AD) are associated with vascular complications and impaired nitric oxide (NO) production. Furthermore, increased ?-site amyloid precursor protein-cleaving (APP-cleaving) enzyme 1 (BACE1), APP, and ?-amyloid (A?) are linked with vascular disease development and increased BACE1 and A? accompany hyperglycemia and hyperlipidemia. However, the causal relationship between obesity and diabetes, increased A?, and vascular dysfunction is unclear. We report that diet-induced obesity (DIO) in mice increased plasma and vascular A?42 that correlated with decreased NO bioavailability, endothelial dysfunction, and increased blood pressure. Genetic or pharmacological reduction of BACE1 activity and A?42 prevented and reversed, respectively, these outcomes. In contrast, expression of human mutant APP in mice or A?42 infusion into control diet-fed mice to mimic obese levels impaired NO production, vascular relaxation, and raised blood pressure. In humans, increased plasma A?42 correlated with diabetes and endothelial dysfunction. Mechanistically, higher A?42 reduced endothelial NO synthase (eNOS), cyclic GMP (cGMP), and protein kinase G (PKG) activity independently of diet, whereas endothelin-1 was increased by diet and A?42. Lowering A?42 reversed the DIO deficit in the eNOS/cGMP/PKG pathway and decreased endothelin-1. Our findings suggest that BACE1 inhibitors may have therapeutic value in the treatment of vascular disease associated with diabetes.

SUBMITTER: Meakin PJ 

PROVIDER: S-EPMC7410081 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature