Role of Reactive Oxygen Species in Postischemic Leukocyte Rolling and Adhesion in Male and Female Plasminogen Activator Inhibitor Type‐1 Knockout Mice

Leukocyte rolling (LR) and adhesion (LA) are markedly elevated in male, but not female, plasminogen activator inhibitor type‐1 knockout (PAI‐1−/−) mice under baseline conditions relative to that noted in wild‐type (WT) animals, effects that are due to enhanced oxidant generation. The current aims were to determine whether ischemia‐reperfusion (I/R)‐induced LR and LA are increased to a greater extent in male vs female PAI‐1−/− mice and whether oxidants mediate these responses. Male and female PAI‐1−/− mice were treated with MnTBAP (cell‐permeable SOD mimetic), oxypurinol (xanthine oxidase (XO) inhibitor), or apocynin (NADPH oxidase (NOX) inhibitor) 1 hr prior to ischemia (45 min) followed by reperfusion (60 min), with postcapillary venular LR and LA quantified using intravital microscopy. Our data indicate that postischemic LR and LA were markedly elevated in male and female PAI‐1−/− mice, relative to that measured in WT mice, but male PAI‐1−/− mice exhibited higher levels than females. These postischemic increases in LR and LA were abolished by treatment with apocynin, oxypurinol or MnTBAP. Thus, male PAI‐1−/− mice exhibit higher levels of postischemic LR and LA than PAI‐1−/− females. However, ROS generated via XO‐ and NOX‐dependent mechanisms appear to play equally prominent roles as mediators of these proinflammatory effects of I/R in both male&female PAI‐1−/− mice. Supported by NIH (HL‐95486).