title: Bendavia restores mitochondrial energy metabolism gene expression and suppresses cardiac fibrosis in the border zone of the infarcted heart.
abstract: OBJECTIVE
  We have observed that Bendavia, a mitochondrial-targeting peptide that binds the phospholipid cardiolipin and stabilizes the components of electron transport and ATP generation, improves cardiac function and prevents left ventricular remodeling in a 6week rat myocardial infarction (MI) model. We hypothesized that Bendavia restores mitochondrial biogenesis and gene expression, suppresses cardiac fibrosis, and preserves sarco/endoplasmic reticulum (SERCA2a) level in the noninfarcted border zone of infarcted hearts.
  
  
  METHODS
  Starting 2h after left coronary artery ligation, rats were randomized to receive Bendavia (3mg/kg/day), water or sham operation. At 6weeks, PCR array and qRT-PCR was performed to detect gene expression. Picrosirius red staining was used to analyze collagen deposition.
  
  
  RESULTS
  There was decreased expression of 70 out of 84 genes related to mitochondrial energy metabolism in the border zone of untreated hearts. This down-regulation was largely reversed by Bendavia treatment. Downregulated mitochondrial biogenesis and glucose & fatty acid (FA) oxidation related genes were restored by administration of Bendavia. Matrix metalloproteinase (MMP9) and tissue inhibitor of metalloproteinase (TIMP1) gene expression were significantly increased in the border zone of untreated hearts. Bendavia completely prevented up-regulation of MMP9, but maintained TIMP1 gene expression. Picrosirius red staining demonstrated that Bendavia suppressed collagen deposition within border zone. In addition, Bendavia showed a trend toward restoring SERCA2a expression.
  
  
  CONCLUSIONS
  Bendavia restored expression of mitochondrial energy metabolism related genes, prevented myocardial matrix remodeling and preserved SERCA2a expression in the noninfarcted border, which may have contributed to the preservation of cardiac structure and function.
authors.affiliation: Huntington Medical Research Institutes, Pasadena, CA, United States; Heart Institute, Good Samaritan Hospital, Los Angeles, CA, United States; Division of Cardiovascular Medicine of the Keck School of Medicine, University of Southern California, Los Angeles, CA, United States. Electronic address: shi@hmri.org.
authors.forename: Jianru
authors.initials: J
authors.lastname: Shi
authors.affiliation: Huntington Medical Research Institutes, Pasadena, CA, United States; Heart Institute, Good Samaritan Hospital, Los Angeles, CA, United States; Division of Cardiovascular Medicine of the Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
authors.forename: Wangde
authors.initials: W
authors.lastname: Dai
authors.affiliation: Huntington Medical Research Institutes, Pasadena, CA, United States; Heart Institute, Good Samaritan Hospital, Los Angeles, CA, United States; Division of Cardiovascular Medicine of the Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Hale
authors.affiliation: Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Brown
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL, United States.
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL, United States.
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
authors.affiliation: Huntington Medical Research Institutes, Pasadena, CA, United States; Heart Institute, Good Samaritan Hospital, Los Angeles, CA, United States; Division of Cardiovascular Medicine of the Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kloner
mesh_terms: D000818:Animals; D002308:Cardiolipins / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects* / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology*; D009206:Myocardium / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000096:biosynthesis / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D002308:Cardiolipins; D005227:Fatty Acids; D009842:Oligopeptides; D019715:Tissue Inhibitor of Metalloproteinase-1; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D003094:Collagen; D020780:Matrix Metalloproteinase 9; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D005947:Glucose
keywords: Bendavia; Cardioprotection; Mitochondria; Myocardial infarction