title: Reduction of early reperfusion injury with the mitochondria-targeting peptide bendavia.
abstract: We recently showed that Bendavia, a novel mitochondria-targeting peptide, reduced infarction and no-reflow across several experimental models. The purpose of this study was to determine the therapeutic timing and mechanism of action that underlie Bendavia's cytoprotective property. In rabbits exposed to in vivo ischemia/reperfusion (30/180 min), Bendavia administered 20 minutes prior to reperfusion (0.05 mg/kg/h, intravenously) reduced myocardial infarct size by ∼50% when administered for either 1 or 3 hours of reperfusion. However, when Bendavia perfusion began just 10 minutes after the onset of reperfusion, the protection against infarction and no-reflow was completely lost, indicating that the mechanism of protection is occurring early in reperfusion. Experiments in isolated mouse liver mitochondria found no discernible effect of Bendavia on blocking the permeability transition pore, and studies in isolated heart mitochondria showed no effect of Bendavia on respiratory rates. As Bendavia significantly lowered reactive oxygen species (ROS) levels in isolated heart mitochondria, the ROS-scavenging capacity of Bendavia was compared to well-known ROS scavengers using in vitro (cell-free) systems that enzymatically generate ROS. Across doses ranging from 1 nmol/L to 1 mmol/L, Bendavia showed no discernible ROS-scavenging properties, clearly differentiating itself from prototypical scavengers. In conclusion, Bendavia is a promising candidate to reduce cardiac injury when present at the onset of reperfusion but not after reperfusion has already commenced. Given that both infarction and no-reflow are related to increased cellular ROS, Bendavia's protective mechanism of action likely involves reduced ROS generation (as opposed to augmented scavenging) by endothelial and myocyte mitochondria.
authors.affiliation: 1Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Brown
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Hale
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Baines
authors.forename: Carlos L
authors.initials: CL
authors.lastname: del Rio
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hamlin
authors.forename: Yukie
authors.initials: Y
authors.lastname: Yueyama
authors.forename: Anusak
authors.initials: A
authors.lastname: Kijtawornrat
authors.forename: Steve T
authors.initials: ST
authors.lastname: Yeh
authors.forename: Chad R
authors.initials: CR
authors.lastname: Frasier
authors.forename: Luke M
authors.initials: LM
authors.lastname: Stewart
authors.forename: Fatiha
authors.initials: F
authors.lastname: Moukdar
authors.forename: Saame Raza
authors.initials: SR
authors.lastname: Shaikh
authors.forename: Kelsey H
authors.initials: KH
authors.lastname: Fisher-Wellman
authors.forename: P Darrell
authors.initials: PD
authors.lastname: Neufer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kloner
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
chemical_list: D016166:Free Radical Scavengers; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009842:Oligopeptides; D017382:Reactive Oxygen Species; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide
keywords: heart; mitochondria; peptide; reactive oxygen species; reperfusion