title: Cardioprotective Effects of Mitochondria-Targeted Peptide SBT-20 in two Different Models of Rat Ischemia/Reperfusion.
abstract: OBJECTIVE
  Dysfunctional mitochondria are considered to be the major source of intracellular reactive oxygen species and play a central role in the pathophysiology of myocardial ischemia/reperfusion. This study sought to determine effects of mitochondria-targeted cytoprotective peptide SBT-20 on myocardial infarct size in two different models of ischemia/reperfusion.
  
  
  METHODS
  For in vivo studies, anesthetized Sprague Dawley rats were subjected to 30 min of coronary artery occlusion followed by 3 h of reperfusion. Rats received saline (control), low dose SBT-20 (0.3 mg/kg/h) or high dose SBT-20 (3 mg/kg/h) treatment (n = 15 rats in each group). Saline or SBT-20 were delivered into the jugular vein starting 5 min after coronary artery occlusion and were continued for one hour post coronary artery reperfusion. Body temperature, heart rate and blood pressure were monitored during the procedure. At the end of 3 h reperfusion, the ischemic risk area, no-reflow area, and infarct size were measured. In separate in vitro studies, isolated rat hearts were exposed to 20 min global ischemia, followed by SBT-20 administration (1 μM) or no SBT-20 (control) throughout the 2 h reperfusion. In vitro studies were conducted in cells and heart mitochondria to ascertain the mitochondrial effects of SBT-20 on mitochondrial respiration and reactive oxygen species production.
  
  
  RESULTS
  In the in vivo study, the ischemic risk areas (as a percentage of the left ventricle) were similar among the saline (49.5 ± 2.3 %), low dose SBT-20 (48.6 ± 2.1 %), and high dose SBT-20 groups (48.7 ± 3.0 %). Treatment with SBT-20 significantly reduced infarct size ( as a percentage of risk area) in low dose (62.1 ± 4.4 %) and high dose (64.0 ± 4.9 %) compared with saline treatment (77.6 ± 2.6 %, p = 0.001 for both doses). There was no difference in infarct size between low and high dose SBT-20 treatment. The no-reflow areas (as a percentage of the risk area) were comparable among the saline (23.9 ± 1.7 %), low dose SBT-20 (23.7 ± 2.8 %), and high dose groups (25.0 ± 2.1 %). Body temperature, heart rate and blood pressure were comparable among the 3 groups at baseline, during ischemia, and at the end of 3 h of reperfusion. In the in vitro study, infarct size was reduced from 43.3 ± 2.6 % in control group (n = 11) to 17.2 ± 2.8 % in the SBT-20 treatment group (n = 5, p < 0.05). There were no benefits of SBT-20 on recovery of left ventricular developed pressure, coronary flow, or maximal rates of contraction/relaxation. In cell studies, treatment with SBT-20 significantly improved maximal mitochondrial respiration in response to an H2O2 challenge. In isolated mitochondria, reactive oxygen species production was significantly blunted following treatment with SBT-20.
  
  
  CONCLUSIONS
  In summary, SBT-20 significantly reduced infarct size in two different models of myocardial injury, but did not affect hemodynamics or no-reflow area in rat heart. The reduction in injury is postulated to involve stabilization of mitochondrial function and reduced mitochondrial production of ROS.
authors.affiliation: HMRI Cardiovascular Research Institute, Huntington Medical Research Institutes, 10 Pico Street, Pasadena, CA, 91105, USA. Wangdedai@yahoo.com.|Division of Cardiovascular Medicine of the Keck School of Medicine, University of Southern California, Los Angeles, California, 90017-2395, USA. Wangdedai@yahoo.com.
authors.forename: Wangde
authors.initials: W
authors.lastname: Dai
authors.affiliation: HMRI Cardiovascular Research Institute, Huntington Medical Research Institutes, 10 Pico Street, Pasadena, CA, 91105, USA.
authors.forename: Elissa
authors.initials: E
authors.lastname: Cheung
authors.affiliation: Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA.
authors.forename: Rick J
authors.initials: RJ
authors.lastname: Alleman
authors.affiliation: Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA.
authors.forename: Justin B
authors.initials: JB
authors.lastname: Perry
authors.affiliation: Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA.
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Allen
authors.affiliation: Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Brown
authors.affiliation: HMRI Cardiovascular Research Institute, Huntington Medical Research Institutes, 10 Pico Street, Pasadena, CA, 91105, USA.|Division of Cardiovascular Medicine of the Keck School of Medicine, University of Southern California, Los Angeles, California, 90017-2395, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kloner
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019069:Cell Respiration / Q000187:drug effects; D003331:Coronary Vessels / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006321:Heart / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D010101:Oxygen Consumption / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D010455:Peptides; D006861:Hydrogen Peroxide
keywords: Cardioprotection; Mitochondria; Myocardial infarction; Peptide