Journal article
Mitochondrial Targeted Antioxidant Peptide Ameliorates Hypertensive Cardiomyopathy
Journal of the American College of Cardiology, Vol.58(1), pp.73-82
06/28/2011
DOI: 10.1016/j.jacc.2010.12.044
PMCID: PMC3742010
PMID: 21620606
Abstract
We investigated the effect of reducing mitochondrial oxidative stress by the mitochondrial-targeted antioxidant peptide SS-31 in hypertensive cardiomyopathy.
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.
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.
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.
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.
Details
- Title: Subtitle
- Mitochondrial Targeted Antioxidant Peptide Ameliorates Hypertensive Cardiomyopathy
- Creators
- Dao-Fu Dai - Department of Pathology, University of Washington, Seattle, WashingtonTony Chen - Department of Pathology, University of Washington, Seattle, WashingtonHazel Szeto - Department of Pharmacology, Weill Cornell Medical College, New York, New YorkMadeline Nieves-Cintrón - Department of Physiology and Biophysics, University of Washington, Seattle, WashingtonVassily Kutyavin - Department of Pathology, University of Washington, Seattle, WashingtonLuis F Santana - Department of Physiology and Biophysics, University of Washington, Seattle, WashingtonPeter S Rabinovitch - Department of Pathology, University of Washington, Seattle, Washington
- Resource Type
- Journal article
- Publication Details
- Journal of the American College of Cardiology, Vol.58(1), pp.73-82
- DOI
- 10.1016/j.jacc.2010.12.044
- PMID
- 21620606
- PMCID
- PMC3742010
- NLM abbreviation
- J Am Coll Cardiol
- ISSN
- 0735-1097
- eISSN
- 1558-3597
- Publisher
- Elsevier Inc
- Grant note
- R01 HL101186; P30 AG013280; P01 AG001751 / National Institutes of Health
- Language
- English
- Date published
- 06/28/2011
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Radiation Oncology
- Record Identifier
- 9984047699802771
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