Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction
| Autor: | Bethany M. Coull, Zofia Tuharska, Ioannis Akoumianakis, Nadira Yuldasheva, Paul J. Meakin, Christopher McCaffery, Jane Brown, Charalambos Antoniades, Moneeza K. Siddiqui, Anna Skromna, Fiona M. Platt, Kathryn J. Griffin, Claire H Ozber, Alison D. McNeilly, Natallia Makava, Colin N. A. Palmer, Faisel Khan, Michael L.J. Ashford, Alan R. Prescott |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Nitric Oxide Synthase Type III Mice Transgenic Nitric oxide 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Endocrinology Enos Vascular Biology Internal medicine Diabetes mellitus Hyperlipidemia mental disorders Cyclic GMP-Dependent Protein Kinases Diabetes Mellitus Medicine Animals Humans Obesity Endothelial dysfunction Amyloid beta-Peptides biology business.industry Vascular disease General Medicine biology.organism_classification medicine.disease Peptide Fragments endothelial cells 3. Good health 030104 developmental biology Blood pressure chemistry 030220 oncology & carcinogenesis Female business cGMP-dependent protein kinase Diabetic Angiopathies Signal Transduction Research Article |
| Zdroj: | The Journal of Clinical Investigation |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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