Mitochondrial Targeted Antioxidant Peptide Ameliorates Hypertensive Cardiomyopathy

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 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 Angiotensin II induces mitochondrial ROS in neonatal cardiomyocytes, which is prevented by SS-31, but not the non-targeted 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 upregulation 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 upregulation, mitochondrial oxidative damage, upregulation of mitochondrial biogenesis, phosphorylation of p38 MAP kinase, and prevented apoptosis, concomitant with amelioration of Ang induced cardiac hypertrophy, diastolic dysfunction, and fibrosis, despite the absence of blood pressure lowering effect. NAC did not show any beneficial effect. 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.

Loss of mitochondrial exo/endonuclease EXOG affects mitochondrial respiration and induces ROS-mediated cardiomyocyte hypertrophy

“…At least for the latter case, we have shown here that scavenging of mitochondrial ROS attenuated hypertrophy development, indicating that ROS is an important driver of hypertrophy in EXOG-depleted cells. This may also be true for other mitochondrial proteins that can stimulate hypertrophy and supports the idea that mitochondrial ROS scavenging may have clinical applications to attenuate cardiac hypertrophy development (3,4).…”

Metabolic abnormalities of the heart in type II diabetes

“…SS-31, MitoQ) preferentially accumulate in mitochondria to reduce ROS generation. 102,103 In cell models of glucotoxicity and gluco-lipotoxicity, MitoQ reduced oxidative stress, increased OxPhos and promoted survival. 102 Alternatively, oxidative stress could be dampened by boosting antioxidant defences with agents such as resveratrol which improved cardiac OxPhos in a rat model of T2DM.…”

Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

“…SS-31 has been shown to mitigate I/R injury and reperfusion arrhythmia and preserve myocardial function in various infarct models (reviewed in 179). Moreover, SS-31 ameliorates cardiomyopathy resulting from prolonged angiotensin-II stimulation and G␣q overexpression in mice, in the absence of any blood pressure lowering effect (35). Euk-8 treatment protects both oxidative stress-prone Harlequin mice and wild-type controls from pressure overload-induced left ventricular remodeling and cardiac decompensation, and extended the overall survival of these animals (202).…”