Oxidative DNA Damage Mediated by Intranuclear MMP Activity Is Associated with Neuronal Apoptosis in Ischemic Stroke

Figure 1

Schematic drawing of hypothesis on how intranuclear MMPs facilitate the oxidative DNA damage and inflammatory cytokines in neurons maturation after ischemic insult. At an early stage after ischemic injury and/or reperfusion, activated nuclear MMPs cleave nuclear proteins PARP-1 and XRCC1, which are critical enzymes in BER pathway for DNA repair and cell suvival. The degradation of these nuclear BER enzymes via MMP-2, activated by furin-enhanced MT1-MMP activity, and MMP-9 during ischemic insult interferes with the DNA repair and enhanced nuclear accumulation of oxidative DNA damage, promoting the ischemic neurons to apoptosis. Intranuclear IL-1β, which rapidly elevates as early as 1 h of stroke, is colocalized with intranucler MMP-2 in neurons, suggesting that MMP-2 may contribute to IL-1β production early after the beginning of reperfusion. Modified from Yang et al. [16].