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Cardiovascular Research 2004 64(3):536-543; doi:10.1016/j.cardiores.2004.08.002
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Amyloid β peptides mediate physiological remodelling of the acute O2 sensitivity of adrenomedullary chromaffin cells following chronic hypoxia

Stephen T. Brown, Rosalyn P. Johnson, Rhandi Senaratne and Ian M. Fearon*

Department of Biology, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada

* Corresponding author. Current address: School of Biological Sciences, The University of Manchester, G. 38 Stopford Building, Oxford Road, Manchester, M13 9PT, UK. Tel.: +44 (0) 161 275 5496; fax: +44 (0) 161 275 5600. Email address: ian.fearon{at}man.ac.uk

Objective: The non-neurogenic response of the neonatal adrenal medulla is vital in cardiovascular and respiratory development and to the survival of newborns exposed to hypoxic stress. Here, we examined the acute hypoxic response of immortalised rat adrenomedullary chromaffin cells following exposure to chronic hypoxia (CH; 6% O2 for 24 h).

Methods: Ca2+ and K+ channel currents were recorded using by whole-cell patch-clamp.

Results: Following incubation in CH, the acute O2 sensitivity of K+ current in immortalised adrenomedullary chromaffin (MAH) cells was enhanced due to a selective increase in the density of an O2-sensitive Ca2+-dependent K+ current, secondary to ROS-mediated augmentation of voltage-gated Ca2+ currents. The effect of CH on Ca2+ currents was not additive to exogenous Aβ1–40 and was blocked by the {gamma}-secretase inhibitors {gamma}-X and {gamma}-VI, demonstrating a role for amyloid β peptide (AβP) production. Ca2+ current enhancement was abolished in the presence of the transcription inhibitor actinomycin D but unaffected by the vacuolar H+ ATPase inhibitor bafilomycin A1.

Conclusion: AβP production and transcriptional regulation during CH regulated the properties of a peripheral chemosensory cell, defining a role for these enigmatic peptides in the signalling pathway of a physiological response to CH in the developing cardiovascular system.

KEYWORDS Hypoxia/anoxia; Ca-channel; K-channel; Developmental biology

Time for primary review 18 days


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