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Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction
Paul J. Meakin, … , Faisel Khan, Michael L.J. Ashford
Paul J. Meakin, … , Faisel Khan, Michael L.J. Ashford
Published May 14, 2020
Citation Information: J Clin Invest. 2020;130(8):4104-4117. https://doi.org/10.1172/JCI122237.
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Research Article Endocrinology Vascular biology

Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction

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Abstract

Diabetes, obesity, and Alzheimer’s disease (AD) are associated with vascular complications and impaired nitric oxide (NO) production. Furthermore, increased β-site amyloid precursor protein–cleaving (APP-cleaving) enzyme 1 (BACE1), APP, and β-amyloid (Aβ) are linked with vascular disease development and increased BACE1 and Aβ accompany hyperglycemia and hyperlipidemia. However, the causal relationship between obesity and diabetes, increased Aβ, and vascular dysfunction is unclear. 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.

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 D. McNeilly, Moneeza Siddiqui, Colin N.A. Palmer, Faisel Khan, Michael L.J. Ashford

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Figure 5

Plasma NOx, ET-1, and aortic cGMP are modified by BACE1 activity and Aβ42.

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Plasma NOx, ET-1, and aortic cGMP are modified by BACE1 activity and Aβ4...
(A) Plasma NOx levels in RC-fed WT, hAPPSw, and BACE1-KO, DIO, and HF-fed BACE1-KO mice (n = 9–14). (B) Plasma NOx levels in RC-fed WT and HF-fed (5 weeks) mice after 4 weeks of Aβ42 or ScrP infusion (n = 4–12). (C) Plasma NOx levels in vehicle- and M-3–treated DIO mice (n = 12–14). (D) Plasma ET-1 levels in RC-fed WT, hAPPSw, and BACE1-KO, DIO, and HF-fed BACE1-KO mice (n = 9–21). (E) Plasma ET-1 levels in RC-fed WT and HF-fed (5 weeks) mice after 4 weeks of Aβ42 or ScrP infusion (n = 4–12). (F) Plasma ET-1 levels in vehicle- and M-3–treated DIO mice (n = 8–18). (G) Aortic cGMP levels in RC-fed WT, hAPPSw, and BACE1-KO, DIO, and HF-fed BACE1-KO mice (n = 6–12). (H) Aortic cGMP levels in HF-fed (5 weeks) mice after 4 weeks of Aβ42 or ScrP infusion (n = 9–10) and (I) in vehicle- and M-3–treated DIO mice (n = 10–11). Data are means ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 by 2-way ANOVA with Tukey’s multiple-comparisons test (A, B, D, E, G, and H) or 2-tailed unpaired Student’s t test (C, F, and I). #P < 0.05 vs. RC-fed WT (A and G).

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