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Amyloid-β peptides activate α1-adrenergic cardiovascular receptors

Item Type:Article
Title:Amyloid-β peptides activate α1-adrenergic cardiovascular receptors
Creators Name:Haase, N. and Herse, F. and Spallek, B. and Haase, H. and Morano, I. and Qadri, F. and Szijártó, I.A. and Rohm, I. and Yilmaz, A. and Warrington, J.P. and Ryan, M.J. and Gollasch, M. and Müller, D.N. and Dechend, R. and Wallukat, G.
Abstract:Alzheimer disease features amyloid-beta (Abeta) peptide deposition in brain and blood vessels and is associated with hypertension. Abeta peptide can cause vasoconstriction and endothelial dysfunction. We observed that Abeta peptides exert a chronotropic effect in neonatal cardiomyocytes, similar to alpha1-adrenergic receptor autoantibodies that we described earlier. Recently, it was shown that alpha1-adrenergic receptor could impair blood-brain flow. We hypothesized that Abeta peptides might elicit a signal transduction pathway in vascular cells, induced by alpha1-adrenergic receptor activation. Abeta (25-35) and Abeta (10-35) induced a positive chronotropic effect in the cardiac contraction assay (28.75+/-1.15 and 29.40+/-0.98 bpm), which was attenuated by alpha1-adrenergic receptor blockers (urapidil, 1.53+/-1.17 bpm; prazosin, 0.30+/-0.96 bpm). Both Abeta peptides induced an intracellular calcium release in vascular smooth muscle cells. Chronotropic activity and calcium response elicited by Abeta (25-35) were blocked with peptides corresponding to the first extracellular loop of the alpha1-adrenergic receptor. We observed an induction of extracellular-regulated kinase 1/2 phosphorylation by Abeta (25-35) in Chinese hamster ovary cells overexpressing alpha1-adrenergic receptor, vascular smooth muscle cells, and cardiomyocytes. We generated an activation-state-sensitive alpha1-adrenergic receptor antibody and visualized activation of the alpha1-adrenergic receptor by Abeta peptide. Abeta (25-35) induced vasoconstriction of mouse aortic rings and in coronary arteries in Langendorff-perfused rat hearts that resulted in decreased coronary flow. Both effects could be reversed by alpha1-adrenergic receptor blockade. Our data are relevant to the association between Alzheimer disease and hypertension. They may explain impairment of vascular responses by Abeta and could have therapeutic implications.
Keywords:{alpha}1-Adrenergic Receptor, Alzheimer Disease, Amyloid-{beta} Peptides, Hypertension, Signal Transduction, Vasoconstriction, Animals, Cricetinae, Mice, Rats
Publisher:American Heart Association
Page Range:966-972
Date:November 2013
Official Publication:https://doi.org/10.1161/HYPERTENSIONAHA.113.01348
PubMed:View item in PubMed

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