Mitochondrial Targeted Antioxidant Peptide Ameliorates Hypertensive Cardiomyopathy

Study Questions:

What is the effect of reducing mitochondrial oxidative stress by the mitochondrial-targeted antioxidant peptide SS-31 in hypertensive cardiomyopathy?


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. One-way analysis of variance was used to compare differences among multiple groups, followed by the Tukey post-hoc test for significance.


Ang induces mitochondrial reactive oxygen species (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, 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.


The authors concluded that mitochondrial targeted peptide SS-31 ameliorates cardiomyopathy resulting from prolonged Ang stimulation as well as Gαq overexpression.


The investigators found that ROS plays an essential role in hypertensive cardiomyopathies downstream of Ang, and protection from mitochondrial ROS by a mitochondrial targeted antioxidant confers resistance to cardiomyopathy, whereas nontargeted antioxidant NAC does not. Furthermore, the study provides direct evidence that Ang induces mitochondrial ROS, which is prevented by SS-31, but not by NAC. The study suggests that a mitochondrial-targeted antioxidant drug is beneficial in preventing hypertension-induced target organ damage, and provides a rationale for investigating targeted cellular antioxidants for the treatment or prevention of hypertensive cardiovascular diseases.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Novel Agents, Acute Heart Failure, Hypertension

Keywords: Apoptosis, Cardiomyopathies, Mitochondrial Proteins, Heart Failure, Myocytes, Cardiac, Hypertension

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