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

Heparinbinding EGF- like growth factor mediates oxyhemoglobin- induced suppression of voltage- dependent potassium channels in rabbit cerebral artery myocytes. Am J Physiol Heart Circ Physiol 293: H1750 - H1759, 2007. First published June 8, 2007; doi: 10.1152/ ajpheart. 00443.2007. - 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 KV 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 KV suppression in rabbit cerebral artery myocytes. KV 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 KV 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 KV current suppression. We also observed KV 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 KV channel suppression. We propose that EGFR- mediated KV 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.