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

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

Effects of Mitochondrial-Targeted Antioxidants on Real-Time Blood Nitric Oxide and Hydrogen Peroxide Release in Acute Hyperglycemia Rats

Acute hyperglycemia in non-diabetic subjects can impair vascularendothelial function, causing decreased endothelium-derived nitric oxide (NO) release and increased reactive oxygen species (ROS), such assuperoxide and hydrogen peroxide (H2O2). Hyperglycemia may induce mitochondrial dysfunction leading to ROS production and exacerbation of vascular endothelial dysfunction. We investigated whether mitochondrial-targeted antioxidants mitigate acute hyperglycemia-induced oxidative stress and reduced blood NO. To test this hypothesis, blood NO or H2O2 levels were measured simultaneously using NO or H2O2 microsensors (100 µm) which were placed into the femoral veins of anesthesized male Sprague-Dawley rats. Acute hyperglycemia was induced by infusion 20% D-glucose intravenously with or without mitochondria-targeted antioxidants (mitoquinone: mitoQ, MW=1714 g/mol, 2.3 mg/Kg; SS-31: (D-Arg)-Dmt-Lys-Phe-Amide, MW=640g/mol, 2.7 mg/Kg) for 3 hours. We found that acute hyperglycemia (200 mg/dL) significantly increased blood H2O2 by 3.0±0.5 M (n=7) and reduced blood NO by 68.0±13.5 nM (n=9) compared to the saline group at end of infusion (both p\u3c0.05). MitoQ significantly attenuated hyperglycemia– induced H2O2 levels by 2.5±0.2 M (n=7) and increased blood NO levels by 59.3±9.7 nM (n=5) (both p\u3c0.05 compared to hyperglycemia). Similarly, SS-31 significantly reduced hyperglycemia-induced blood H2O2 level by 4.0±0.6 M (n=5) and enhanced blood NO levels by 52.8±7.7 nM (n=6) at end of infusion (both p\u3c0.05 compared to hyperglycemia). In summary, acute hyperglycemia induces mitochondria-derived ROS which in turn contribute to vascular endothelial dysfunction. Therefore, mitochondria-targeted antioxidants are useful to attenuate acute hyperglycemia-induced vascular endothelial dysfunction and oxidative stress

Gp91ds-tat, a Selective NADPH Oxidase Peptide Inhibitor, Increases Blood Nitric Oxide (NO) Bioavailability in Bind Limb Ischemia and Reperfusion (I/R)

I/R injury induces cell death and organ dysfunction in part due to a burst of reactive oxygen species that occurs upon the reintroduction of oxygen into the ischemic area, leading to endothelial dysfunction: decreased blood NO and increased hydrogen peroxide (H2O2 ) levels. We’ve previously shown in isolated rat hearts subjected to I/R injury, gp91ds-tat attenuated cardiac contractile dysfunction and reduced infarct size compared to controls presumably by the inhibition of NADPH oxidase induced superoxide release. Superoxide can quench NO via the formation of peroxynitrite and also be converted to H2O2 in blood. We attempted to confirm this hypothesis using a rat hind limb I/R model that permitted real time measurements of changes in blood NO and H2O2. NO or H2O2 microsensors were inserted into both femoral veins in anesthetized male rats. One limb’s femoral artery/vein is subjected to I(30min)/R(45min) while the other served as a non-ischemic sham. Preliminary results show blood NO release significantly increased by the end of reperfusion in gp91ds-tat treated rats (1.2 mg/kg, MW 2452g/mol, n=5) compared to saline treated rats (n=3;

Cardioprotective Effects of Selective Mitochondrial-Targeted Antioxidants in Myocardial Ischemia/Reperfusion (I/R) Injury

During myocardial ischemia, coronary blood flow interruption deprives cardiomyocytes of oxygen, glucose and fatty acids. Ischemic damage is exacerbated by a burst of reactive oxygen species (ROS) generated at reperfusion when oxygen interacts with damaged mitochondrial electron transport chains (ETC), especially uncoupled complexes I and III (Fig. 1,2). Nicotinamide adenine dinucleotide phosphate oxidase (Nox) activity can also release ROS, inducing additional tissue/organ damage. Surgical intervention or thrombolytic treatments can restore coronary blood flow. However, as blood flow reestablishes, oxidative stress leads to I/R injury. Clinical treatment remains a challenge as no pharmaceutical agents effectively limit I/R-induced damage. Mitochondria are implicated in I/R as a major source of ROS3,4,5. Excess ROS leads to mitochondrial and cardiac contractile dysfunction6. Conventional antioxidants have limited efficacy in myocardial I/R because they are not targeted selectively to where most I/R damage occurs, in mitochondria (Fig. 3)3,4,5. Mitoquinone (mitoQ, MW=600 g/mol), a coenzyme Q analog, easily crosses phospholipid bilayers and is driven by the large electrochemical membrane potential to concentrate mitoQ several hundred-fold within mitochondria. The respiratory chain reduces mitoQ to its active ubiquinol antioxidant form to limit myocardial I/R injury5. The SS-31 (Szeto-Schiller) peptide ((D-Arg)-Dmt-Lys-Phe-Amide, MW=640 g/mol, Genemed Synthesis, Inc., San Antonio, TX) is also of interest since it is cellpermeable, specifically targeted to inner mitochondrial membranes based on its alternating cationic aromatic residue sequence, with an antioxidant dimethyltyrosine moeity. SS peptides scavenge ROS in I/R models. Although mitochondrial-targeted antioxidant pretreatment can effectively limit I/R injury, pretreatment is not always possible in cases of myocardial infarction. Therefore, evaluating cardioprotective efficacy of mitochondrialtargeted antioxidants when given at reperfusion is of high significanc

Expressions 1985

PRODUCTION STAFFLOUISE AUSTINDANA Z. BEHRENDSENAMBER HEWITTTOSHIA SOUTHRANDY STANDLEYSHELLY WILSONhttps://openspace.dmacc.edu/expressions/1006/thumbnail.jp

Procedural justice in procurement management and inclusive interorganizational relations:An institutional perspective

This paper applies the concept of procedural justice to one of the most important focal points of interorganizational relations: the purchaser-supplier relationship. The few extant studies of the concept in the purchaser-supplier domain have overlooked an important aspect of this key relationship: that is, inclusiveness in procurement. This is despite the fact that interest in the specific empirical context of supply chain links between large purchasing organizations (LPOs) and ethnic minority suppliers (EMSs) from disadvantaged communities proceeds apace on both sides of the Atlantic. Institutional theory is used to examine the form that procedural justice takes in eight case studies of LPOs from the private and public sectors, which actively engage with inclusive procurement management initiatives in England. The guiding question is twofold: 'What may LPO approaches to installing procedural justice in procurement management entail?' and 'How are these approaches shaped?' This paper identifies specific approaches to installing procedural justice for inclusive procurement and submits theoretical propositions about how these are shaped. The study contributes to a macro-level assessment of procedural justice, i.e. interorganizational procedural justice, as a significant aspect of inclusive interorganizational relationships, which is a domain in need of theoretical development

The effects of climate change policy on the business community: a corporate environmental accounting perspective

This paper proposes a normative framework to explain the influence of climate change policy on corporate environmental strategies, and at the same time describes how these strategies could be translated into an integrated environmental accounting model based on formal accounting statements. In particular, it aims to demonstrate a new approach of climate change accounting in order to overcome some important weaknesses of previous environmental accounting methods, such as accuracy and reliability. Currently, the majority of existing accounting methods record information on climate change on a voluntary basis. Even though they may assist businesses in designing essential environmental strategies and help public policy entities improve their knowledge on the results of such strategies, the informal nature of the accounting standards and the variable type of financial and non-financial information make the use of such models untrustworthy and complicated. Finally, an empirical example of this framework is also presented. Copyright © 2015 John Wiley & Sons, Ltd and ERP Environment