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

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 2

Loss of BACE1 prevents HF feeding–induced endothelial and vascular smooth muscle dysfunction.

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Loss of BACE1 prevents HF feeding–induced endothelial and vascular smoot...
(A) Endothelium-dependent microvascular responses induced by ACh in RC-fed WT, DIO (20-week HF-fed) mice, and RC- and HF-fed BACE1-KO mice (n = 10–21). PE, phenylephrine. (B) Quantitative analysis of ACh response from A. (C) Endothelium-independent responses induced by SNP in RC-WT, DIO, and BACE1-KO mice (n = 8–9). (D) Quantitative analysis of SNP responses from C. (E) Microvascular responses induced by ACh in the presence of L-NAME in RC-fed WT, DIO, and RC- and HF-fed WT and BACE1-KO mice (n = 6–10). (F) Quantitative analysis of ACh responses from E. The broken line denotes the RC-fed WT ACh response. (G) Microvascular responses to localized heating in RC-fed WT, DIO, and RC- and HF-fed BACE1-KO mice (n = 9–11). (H) Quantitative analysis of heating responses from G. Data are means ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 by 2-way ANOVA with Tukey’s multiple-comparisons test.