SAH-induced MMP activation and K V current suppression is mediated via both ROS-dependent and ROS-independent...

Area of Science:

• Neuroscience
• Cardiovascular Physiology
• Molecular Biology

Background:

• Voltage-gated potassium (K V) channels are crucial for regulating cerebral artery tone.
• Subarachnoid hemorrhage (SAH) is associated with pathologies involving K V channels.
• Matrix metalloproteases (MMPs) and epidermal growth factor receptors (EGFRs) are implicated in SAH-induced vascular dysfunction.

Purpose of the Study:

• To investigate the role of MMP activation in SAH-induced suppression of K V currents and cerebral artery constriction.
• To determine if EGFR activation mediates SAH-induced K V current suppression.
• To elucidate the pathways through which oxyhemoglobin (OxyHb) affects K V currents in the context of SAH.

Main Methods:

• Patch clamp electrophysiology was used to measure K V currents in cerebral artery myocytes from SAH model rabbits.
• Gelatin zymography was employed to assess MMP-2 activity.
• Pharmacological inhibitors and scavengers were used to investigate the roles of MMPs, EGFRs, and reactive oxygen species (ROS).

Main Results:

• K V currents were significantly decreased in cerebral artery myocytes following SAH.
• OxyHb and HB-EGF did not further suppress K V currents after SAH, suggesting involvement of endogenous pathways.
• MMP-2 activity was elevated after SAH, and MMP inhibition blocked OxyHb-induced K V current suppression.
• ROS scavengers partially inhibited OxyHb-induced K V current suppression but not MMP-2 activation.

Conclusions:

• OxyHb suppresses K V currents in cerebral arteries through both ROS-dependent and ROS-independent pathways.
• MMP activation, particularly MMP-2, is a key mediator of SAH-induced K V current suppression.
• The ROS-independent pathway involves MMP-2, while the ROS-dependent pathway may involve other MMPs or ADAMs.