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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/H1750    most recent 00443.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Koide, M. Articles by Wellman, G. C. Search for Related Content PubMed PubMed Citation Articles by Koide, M. Articles by Wellman, G. C.

Heparin-binding EGF-like growth factor mediates oxyhemoglobin-induced suppression of voltage-dependent potassium channels in rabbit cerebral artery myocytes

¹Department of Pharmacology, University of Vermont College of Medicine, and ²Department of Surgery, Division of Neurosurgery, University of Vermont College of Medicine, Burlington, Vermont

Submitted 11 April 2007 ; accepted in final form 7 June 2007

Oxyhemoglobin (OxyHb) can suppress voltage-dependent K⁺ channel (K_V) currents through protein tyrosine kinase activation, which may contribute to cerebral vasospasm following subarachnoid hemorrhage. Here we have tested the hypothesis that shedding of heparin-binding EGF-like growth factor (HB-EGF) and the resulting activation of the tyrosine kinase EGF receptor (EGFR) underlie OxyHb-induced K_V channel suppression in the cerebral vasculature. With the use of the conventional whole cell patch-clamp technique, two EGFR ligands, EGF and HB-EGF, were found to mimic OxyHb-induced K_V suppression in rabbit cerebral artery myocytes. K_V current suppression by OxyHb or EGF ligands was eliminated by a specific EGFR inhibitor, AG-1478, but was unaffected by PKC inhibition. Compounds (heparin and CRM-197) that specifically interfere with HB-EGF signaling eliminated OxyHb-induced K_V suppression, suggesting that HB-EGF is the EGFR ligand involved in this pathway. HB-EGF exists as a precursor protein that, when cleaved by matrix metalloproteases (MMPs), causes EGFR activation. MMP activation was detected in OxyHb-treated arteries by gelatin zymography. Furthermore, the MMP inhibitor (GM-6001) abolished OxyHb-induced K_V current suppression. We also observed K_V current suppression due to EGFR activation in human cerebral artery myocytes. In conclusion, these data demonstrate that OxyHb induces MMP activation, causing HB-EGF shedding and enhanced EGFR activity, ultimately leading to K_V channel suppression. We propose that EGFR-mediated K_V suppression contributes to vascular pathologies, such as cerebral vasospasm, and may play a more widespread role in the regulation of regional blood flow and peripheral resistance.

vascular smooth muscle; growth factors; subarachnoid hemorrhage; tyrosine kinase

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