title: Mitochondrial targeted antioxidant Peptide ameliorates hypertensive cardiomyopathy.
abstract: OBJECTIVE
  We investigated the effect of reducing mitochondrial oxidative stress by the mitochondrial-targeted antioxidant peptide SS-31 in hypertensive cardiomyopathy.
  
  
  BACKGROUND
  Oxidative stress has been implicated in hypertensive cardiovascular diseases. Mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase have been proposed as primary sites of reactive oxygen species (ROS) generation.
  
  
  METHODS
  The mitochondrial targeted antioxidant peptide SS-31 was used to determine the role of mitochondrial oxidative stress in angiotensin II (Ang)-induced cardiomyopathy as well as in Gαq overexpressing mice with heart failure.
  
  
  RESULTS
  Ang induces mitochondrial ROS in neonatal cardiomyocytes, which is prevented by SS-31, but not the nontargeted antioxidant N-acetyl cysteine (NAC). Continuous administration of Ang for 4 weeks in mice significantly increased both systolic and diastolic blood pressure, and this was not affected by SS-31 treatment. Ang was associated with up-regulation of NADPH oxidase 4 (NOX4) expression and increased cardiac mitochondrial protein oxidative damage, and induced the signaling for mitochondrial biogenesis. Reducing mitochondrial ROS by SS-31 substantially attenuated Ang-induced NOX4 up-regulation, mitochondrial oxidative damage, up-regulation of mitochondrial biogenesis, and phosphorylation of p38 mitogen-activated protein kinase and prevented apoptosis, concomitant with amelioration of Ang-induced cardiac hypertrophy, diastolic dysfunction, and fibrosis, despite the absence of blood pressure-lowering effect. The NAC did not show any beneficial effect. The SS-31 administration for 4 weeks also partially rescued the heart failure phenotype of Gαq overexpressing mice.
  
  
  CONCLUSIONS
  Mitochondrial targeted peptide SS-31 ameliorates cardiomyopathy resulting from prolonged Ang stimulation as well as Gαq overexpression, suggesting its potential clinical application for target organ protection in hypertensive cardiovascular diseases.
authors.affiliation: Department of Pathology, University of Washington, 1959 Pacific Avenue Northeast, Seattle, WA 98195, USA.
authors.forename: Dao-Fu
authors.initials: DF
authors.lastname: Dai
authors.forename: Tony
authors.initials: T
authors.lastname: Chen
authors.forename: Hazel
authors.initials: H
authors.lastname: Szeto
authors.forename: Madeline
authors.initials: M
authors.lastname: Nieves-Cintrón
authors.forename: Vassily
authors.initials: V
authors.lastname: Kutyavin
authors.forename: Luis F
authors.initials: LF
authors.lastname: Santana
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis; D020935:MAP Kinase Signaling System; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology; D019255:NADPH Oxidases / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism*; D018384:Oxidative Stress; D010455:Peptides / Q000737:chemistry*; D010641:Phenotype; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D009842:Oligopeptides; D010455:Peptides; D017382:Reactive Oxygen Species; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases