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?

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

Results:

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.

Conclusions:

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

Perspective:

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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