title: SAH-induced MMP activation and K V current suppression is mediated via both ROS-dependent and ROS-independent mechanisms.
abstract: Voltage-gated potassium (K V) channels regulate cerebral artery tone and have been implicated in subarachnoid hemorrhage (SAH)-induced pathologies. Here, we examined whether matrix metalloprotease (MMP) activation contributes to SAH-induced K V current suppression and cerebral artery constriction via activation of epidermal growth factor receptors (EGFRs). Using patch clamp electrophysiology, we observed that K V currents were selectively decreased in cerebral artery myocytes isolated from SAH model rabbits. Consistent with involvement of enhanced MMP and EGFR activity in SAH-induced K V current suppression, we found that: (1) oxyhemoglobin (OxyHb) and/or the exogenous EGFR ligand, heparin-binding EGF-like growth factor (HB-EGF), failed to induce further K V current suppression after SAH and (2) gelatin zymography detected significantly higher MMP-2 activity after SAH. The removal of reactive oxygen species (ROS) by combined treatment with superoxide dismutase (SOD) and catalase partially inhibited OxyHb-induced K V current suppression. However, these agents had little effect on OxyHb-induced MMP-2 activation. Interestingly, in the presence of a broad-spectrum MMP inhibitor (GM6001), OxyHb failed to cause K V current suppression. These data suggest that OxyHb suppresses K V currents through both ROS-dependent and ROS-independent pathways involving MMP activation. The ROS-independent pathway involves activation of MMP-2, whereas the ROS-dependent pathway involves activation of a second unidentified MMP or ADAM (a disintegrin and metalloprotease domain).
authors.affiliation: Department of Pharmacology, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, USA, masayo.koide@uvm.edu.
authors.forename: Masayo
authors.initials: M
authors.lastname: Koide
authors.forename: George C
authors.initials: GC
authors.lastname: Wellman
mesh_terms: D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor / Q000378:metabolism / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D010108:Oxyhemoglobins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*
chemical_list: D004151:Dipeptides; D066257:Heparin-binding EGF-like Growth Factor; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D010108:Oxyhemoglobins; D024642:Potassium Channels, Voltage-Gated; D017382:Reactive Oxygen Species; D066246:ErbB Receptors; D020778:Matrix Metalloproteinase 2