title: Amyloid-β peptides activate α1-adrenergic cardiovascular receptors.
abstract: Alzheimer disease features amyloid-β (Aβ) peptide deposition in brain and blood vessels and is associated with hypertension. Aβ peptide can cause vasoconstriction and endothelial dysfunction. We observed that Aβ peptides exert a chronotropic effect in neonatal cardiomyocytes, similar to α1-adrenergic receptor autoantibodies that we described earlier. Recently, it was shown that α1-adrenergic receptor could impair blood-brain flow. We hypothesized that Aβ peptides might elicit a signal transduction pathway in vascular cells, induced by α1-adrenergic receptor activation. Aβ (25-35) and Aβ (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 α1-adrenergic receptor blockers (urapidil, 1.53±1.17 bpm; prazosin, 0.30±0.96 bpm). Both Aβ peptides induced an intracellular calcium release in vascular smooth muscle cells. Chronotropic activity and calcium response elicited by Aβ (25-35) were blocked with peptides corresponding to the first extracellular loop of the α1-adrenergic receptor. We observed an induction of extracellular-regulated kinase 1/2 phosphorylation by Aβ (25-35) in Chinese hamster ovary cells overexpressing α1-adrenergic receptor, vascular smooth muscle cells, and cardiomyocytes. We generated an activation-state-sensitive α1-adrenergic receptor antibody and visualized activation of the α1-adrenergic receptor by Aβ peptide. Aβ (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 α1-adrenergic receptor blockade. Our data are relevant to the association between Alzheimer disease and hypertension. They may explain impairment of vascular responses by Aβ and could have therapeutic implications.
authors.affiliation: Experimental and Clinical Research Center, Lindenberger Weg 80, 13125 Berlin, Germany. ralf.dechend@charite.de.
authors.forename: Nadine
authors.initials: N
authors.lastname: Haase
authors.forename: Florian
authors.initials: F
authors.lastname: Herse
authors.forename: Bastian
authors.initials: B
authors.lastname: Spallek
authors.forename: Hannelore
authors.initials: H
authors.lastname: Haase
authors.forename: Ingo
authors.initials: I
authors.lastname: Morano
authors.forename: Fatimunnisa
authors.initials: F
authors.lastname: Qadri
authors.forename: István A
authors.initials: IA
authors.lastname: Szijártó
authors.forename: Ilonka
authors.initials: I
authors.lastname: Rohm
authors.forename: Atilla
authors.initials: A
authors.lastname: Yilmaz
authors.forename: Junie P
authors.initials: JP
authors.lastname: Warrington
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ryan
authors.forename: Maik
authors.initials: M
authors.lastname: Gollasch
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Müller
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
authors.forename: Gerd
authors.initials: G
authors.lastname: Wallukat
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology*; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; C407125:amyloid beta-protein (10-35); C074636:amyloid beta-protein (25-35); C015568:urapidil
keywords: Alzheimer disease; amyloid-β peptides; hypertension; signal transduction; vasoconstriction; α1-adrenergic receptor