Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction

We report that diet-induced obesity (DIO) in mice increased plasma and vascular Aβ42 that correlated with decreased NO bioavailability, endothelial dysfunction, and increased blood pressure. Genetic or pharmacological reduction of BACE1 activity and Aβ42 prevented and reversed, respectively, these outcomes. In contrast, expression of human mutant APP in mice or Aβ42 infusion into control diet–fed mice to mimic obese levels impaired NO production, vascular relaxation, and raised blood pressure. In humans, increased plasma Aβ42 correlated with diabetes and endothelial dysfunction. Mechanistically, higher Aβ42 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 Aβ42. Lowering Aβ42 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.

Source: Journal of Clinical Investigation - June 29, 2020 Category: Biomedical Science Authors: Paul J. Meakin, Bethany M. Coull, Zofia Tuharska, Christopher McCaffery, Ioannis Akoumianakis, Charalambos Antoniades, Jane Brown, Kathryn J. Griffin, Fiona Platt, Claire H. Ozber, Nadira Y. Yuldasheva, Natallia Makava, Anna Skromna, Alan Prescott, Alison Source Type: research