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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

This article has been cited by other articles:

				T. E. Link, K. Murakami, M. Beem-Miller, B. I. Tranmer, and G. C. Wellman Oxyhemoglobin-Induced Expression of R-Type Ca2+ Channels in Cerebral Arteries Stroke, July 1, 2008; 39(7): 2122 - 2128. [Abstract] [Full Text] [PDF]