Mitochondrial targeted antioxidant peptide ameliorates hypertensive cardiomyopathy

Dao Fu Dai, Tony Chen, Hazel Szeto, Madeline Nieves-Cintrón, Vassily Kutyavin, Luis F. Santana, Peter S. Rabinovitch

Research output: Contribution to journalArticle

204 Citations (Scopus)

Abstract

Objectives: 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.

Original languageEnglish (US)
Pages (from-to)73-82
Number of pages10
JournalJournal of the American College of Cardiology
Volume58
Issue number1
DOIs
StatePublished - Jun 28 2011
Externally publishedYes

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Cardiomyopathies
Reactive Oxygen Species
Oxidative Stress
Up-Regulation
Antioxidants
Organelle Biogenesis
Blood Pressure
NADP
Peptides
Cysteine
Oxidoreductases
Cardiovascular Diseases
Heart Failure
NADPH Oxidase
Mitochondrial Proteins
Cardiomegaly
p38 Mitogen-Activated Protein Kinases
Cardiac Myocytes
Angiotensin II
Mitochondria

Keywords

  • cardiomyopathy
  • hypertension
  • mitochondria

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Mitochondrial targeted antioxidant peptide ameliorates hypertensive cardiomyopathy. / Dai, Dao Fu; Chen, Tony; Szeto, Hazel; Nieves-Cintrón, Madeline; Kutyavin, Vassily; Santana, Luis F.; Rabinovitch, Peter S.

In: Journal of the American College of Cardiology, Vol. 58, No. 1, 28.06.2011, p. 73-82.

Research output: Contribution to journalArticle

Dai, Dao Fu ; Chen, Tony ; Szeto, Hazel ; Nieves-Cintrón, Madeline ; Kutyavin, Vassily ; Santana, Luis F. ; Rabinovitch, Peter S. / Mitochondrial targeted antioxidant peptide ameliorates hypertensive cardiomyopathy. In: Journal of the American College of Cardiology. 2011 ; Vol. 58, No. 1. pp. 73-82.
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AU - Santana, Luis F.

AU - Rabinovitch, Peter S.

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