Reduction of Ischemia/Reperfusion Injury With Bendavia, a Mitochondria‐Targeting Cytoprotective Peptide

Abstract

BackgroundManifestations of reperfusion injury include myocyte death leading to infarction, contractile dysfunction, and vascular injury characterized by the “no-reflow” phenomenon. Mitochondria-produced reactive oxygen species are believed to be centrally involved in each of these aspects of reperfusion injury, although currently no therapies reduce reperfusion injury by targeting mitochondria specifically.Methods and ResultsWe investigated the cardioprotective effects of a mitochondria-targeted peptide, Bendavia (Stealth Peptides), across a spectrum of experimental cardiac ischemia/reperfusion models. Postischemic administration of Bendavia reduced infarct size in an in vivo sheep model by 15% (P=0.02) and in an ex vivo guinea pig model by 38% to 42% (P<0.05). In an in vivo rabbit model, the extent of coronary no-reflow was assessed with Thioflavin S staining and was significantly smaller in the Bendavia group for any given ischemic risk area than in the control group (P=0.0085). Myocardial uptake of Bendavia was ≈25% per minute, and uptake remained consistent throughout reperfusion. Postischemic recovery of cardiac hemodynamics was not influenced by Bendavia in any of the models studied. Isolated myocytes exposed to hypoxia/reoxygenation showed improved survival when treated with Bendavia. This protection appeared to be mediated by lowered reactive oxygen species–mediated cell death during reoxygenation, associated with sustainment of mitochondrial membrane potential in Bendavia-treated myocytes.ConclusionsPostischemic administration of Bendavia protected against reperfusion injury in several distinct models of injury. These data suggest that Bendavia is a mitochondria-targeted therapy that reduces reperfusion injury by maintaining mitochondrial energetics and suppressing cellular reactive oxygen species levels. (J Am Heart Assoc. 2012;1:e001644 doi: 10.1161/JAHA.112.001644.)

Induction of cardioprotection by small netrin-1-derived peptides

“…None of the proposed regiments have been approved by the Food and Drug Administration to treat cardiac I/R injury in the past two decades, including some peptides that have been shown to be beneficial in animal studies (4,7,14). There is still an urgent need for development of an effective cardioprotective agent that can be easily translated into clinical practice.…”

Mitochondria-targeted peptides prevent on contrast-induced acute kidney injury in the rats with hypercholesterolemia

“…These peptides have demonstrated excellent efficacy in animal models of ischemia-reperfusion, neurodegeneration, and renal fibrosis. 7,8 However, the protective effect of mitochondria-targeted peptides (MTP) on CIAKI was unclear. Therefore, the aim of this study was to explore the protective role of MTP on CIAKI in rats with hypercholesterolemia.…”

Protein Kinase C Epsilon PeptideInhibitor Exerts Cardioprotective Effects in Myocardial Ischemia/Reperfusion Injury

“…By contrast, hearts subjected to the lower concentration of Myr-PKCε-(5 µM) may reduce ROS production to a level that attenuates infarct size, but not sufficient to improve post-reperfused cardiac function (see LVDP, +dP/dt max and -dP/ dt min data in Table 1). We surmise that the salvaged cardiomyocytes would exhibit improved contractile function after stunning subsides, which could occur days to weeks after ischemic insult in vivo [40]. Further chronic myocardial I/R studies using Myr-PKCε-(5 µM) are needed in vivo to determine if stunning subsides after treatment.…”

“…5 µM) that cause stunning. Previous myocardial I/R studies using a ROS-reducing antioxidant peptide targeted to the mitochondria have also reported a reduction in infarct size without improvement in contractility lasting days to weeks after reperfusion [40]. Moderately elevated levels of ROS could potentially contribute to stunning of reversibly damaged myocardial tissue while higher levels lead to necrosis.…”