Koide Masayo, Wellman George C
Department of Pharmacology, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, USA,
Acta Neurochir Suppl. 2015;120:89-94. doi: 10.1007/978-3-319-04981-6_15.
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).
电压门控钾（KV）通道调节脑动脉张力，并与蛛网膜下腔出血（SAH）诱发的病变有关。在此，我们研究了基质金属蛋白酶（MMP）激活是否通过激活表皮生长因子受体（EGFR）促成SAH诱导的KV电流抑制和脑动脉收缩。运用膜片钳电生理学技术，我们观察到从SAH模型兔分离的脑动脉肌细胞中KV电流选择性降低。与MMP和EGFR活性增强参与SAH诱导的KV电流抑制一致，我们发现：（1）氧合血红蛋白（OxyHb）和/或外源性EGFR配体肝素结合表皮生长因子样生长因子（HB-EGF）在SAH后未能诱导进一步的KV电流抑制，以及（2）明胶酶谱法检测到SAH后MMP-2活性显著更高。通过超氧化物歧化酶（SOD）和过氧化氢酶联合处理去除活性氧（ROS）可部分抑制OxyHb诱导的KV电流抑制。然而，这些试剂对OxyHb诱导的MMP-2激活几乎没有影响。有趣的是，在存在广谱MMP抑制剂（GM6001）的情况下，OxyHb未能引起KV电流抑制。这些数据表明，OxyHb通过涉及MMP激活的ROS依赖性和ROS非依赖性途径抑制KV电流。ROS非依赖性途径涉及MMP-2的激活，而ROS依赖性途径涉及另一种未鉴定的MMP或ADAM（一种去整合素和金属蛋白酶结构域）的激活。
