Effects of Mitoehondrial-Targeted Antioxidants on Real-Time Nitric Oxide and Hydrogen Peroxide Release in Hind Limb Ischemia and Reperfusion (I/R)

摘要

In the body, reperfusion of ischemic tissue with blood causes the release of reactive oxygen species (ROS), in part, from damaged mitochondria leading to endothelial and organ dysfunction. Endothelial dysfunction occurs within 5 min of reperfusion, is common to all vascular beds, and is characterized by increased hydrogen peroxide (H2O2) and decreased nitric oxide (NO) levels in the blood that further exacerbate I/R injury. Previous studies have shown that promoting endothelial NO synthase coupling during reperfusion increases blood NO and decreases blood H2O2 levels in hind limb I/R and attenuates myocardial I/R injury [1]. This study examines the effectiveness of mitochondria-targeted antioxidants, mitoqui-none (mitoQ), a cell permeable coenzyme Q analogue or SS-31 ((D-Arg)-Dmt-Lys-Phe-Amide; Genemed Synthesis, San Antonio, TX), a cell permeable peptide, in inhibiting H2O2 release and increasing NO bioavailability in hind limb I/R. MitoQ [2] and SS-31 [3] are able to concentrate into the inner mitochondrial membrane via an electrical potential gradient or selective diffusion respectively (Figure 1). We hypothesized that these mitochondria-targeted agents will attenuate superoxide and subsequent H2O2 production thus allowing an increase in NO bioavailability, reducing I/R injury.