Effects of Mitochondria-Targeted Antioxidants on Real-time Blood Nitric Oxide and Hydrogen Peroxide Release in Hind Limb Ischemia and Reperfusion

Philadelphia Campus

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 reperfusion 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 specifically examines the effects mitochondria-targeted antioxidants, mitoquinone (mitoQ; Fig. 1), a cell permeable coenzyme Q analogue or SS-31 ((D-Arg)-Dmt-Lys-Phe-Amide; Genemed Synthesis, San Antonio, TX) (Fig.1), a cell permeable peptide, on inhibiting H2O2 release and increasing NO bioavailability in hind limb I/R. MitoQ (2) and SS-31 (3,4) are able to concentrate into the inner mitochondrial membrane via an electrical potential gradient or selective diffusion respectively, where they attenuate superoxide and subsequent H2O2 production thus allowing a concurrent increase in NO bioavailability.