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Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction

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...

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Autores principales: Meakin, Paul J., Coull, Bethany M., Tuharska, Zofia, McCaffery, Christopher, Akoumianakis, Ioannis, Antoniades, Charalambos, Brown, Jane, Griffin, Kathryn J., Platt, Fiona, Ozber, Claire H., Yuldasheva, Nadira Y., Makava, Natallia, Skromna, Anna, Prescott, Alan, McNeilly, Alison D., Siddiqui, Moneeza, Palmer, Colin N.A., Khan, Faisel, Ashford, Michael L.J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410081/
https://www.ncbi.nlm.nih.gov/pubmed/32407295
http://dx.doi.org/10.1172/JCI122237
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author Meakin, Paul J.
Coull, Bethany M.
Tuharska, Zofia
McCaffery, Christopher
Akoumianakis, Ioannis
Antoniades, Charalambos
Brown, Jane
Griffin, Kathryn J.
Platt, Fiona
Ozber, Claire H.
Yuldasheva, Nadira Y.
Makava, Natallia
Skromna, Anna
Prescott, Alan
McNeilly, Alison D.
Siddiqui, Moneeza
Palmer, Colin N.A.
Khan, Faisel
Ashford, Michael L.J.
author_facet Meakin, Paul J.
Coull, Bethany M.
Tuharska, Zofia
McCaffery, Christopher
Akoumianakis, Ioannis
Antoniades, Charalambos
Brown, Jane
Griffin, Kathryn J.
Platt, Fiona
Ozber, Claire H.
Yuldasheva, Nadira Y.
Makava, Natallia
Skromna, Anna
Prescott, Alan
McNeilly, Alison D.
Siddiqui, Moneeza
Palmer, Colin N.A.
Khan, Faisel
Ashford, Michael L.J.
author_sort Meakin, Paul J.
collection PubMed
description 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.
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spelling pubmed-74100812020-08-07 Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction Meakin, Paul J. Coull, Bethany M. Tuharska, Zofia McCaffery, Christopher Akoumianakis, Ioannis Antoniades, Charalambos Brown, Jane Griffin, Kathryn J. Platt, Fiona Ozber, Claire H. Yuldasheva, Nadira Y. Makava, Natallia Skromna, Anna Prescott, Alan McNeilly, Alison D. Siddiqui, Moneeza Palmer, Colin N.A. Khan, Faisel Ashford, Michael L.J. J Clin Invest Research Article 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. American Society for Clinical Investigation 2020-06-29 2020-08-03 /pmc/articles/PMC7410081/ /pubmed/32407295 http://dx.doi.org/10.1172/JCI122237 Text en © 2020 Meakin et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research Article
Meakin, Paul J.
Coull, Bethany M.
Tuharska, Zofia
McCaffery, Christopher
Akoumianakis, Ioannis
Antoniades, Charalambos
Brown, Jane
Griffin, Kathryn J.
Platt, Fiona
Ozber, Claire H.
Yuldasheva, Nadira Y.
Makava, Natallia
Skromna, Anna
Prescott, Alan
McNeilly, Alison D.
Siddiqui, Moneeza
Palmer, Colin N.A.
Khan, Faisel
Ashford, Michael L.J.
Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction
title Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction
title_full Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction
title_fullStr Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction
title_full_unstemmed Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction
title_short Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction
title_sort elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410081/
https://www.ncbi.nlm.nih.gov/pubmed/32407295
http://dx.doi.org/10.1172/JCI122237
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