SS31 Alleviates Pressure Overload-Induced Heart Failure Caused by Sirt3-Mediated Mitochondrial Fusion

Abstract

Heart failure caused by pressure overload is one of the leading causes of heart failure worldwide, but its pathological origin remains poorly understood. It remains critical to discover and find new improvements and treatments for pressure overload-induced heart failure. According to previous studies, mitochondrial dysfunction and myocardial interstitial fibrosis are important mechanisms for the development of heart failure. The oligopeptide Szeto-Schiller Compound 31 (SS31) can specifically interact with the inner mitochondrial membrane and affect the integrity of the inner mitochondrial membrane. Whether SS31 alleviates pressure overload-induced heart failure through the regulation of mitochondrial fusion has not yet been confirmed. We established a pressure-overloaded heart failure mouse model through TAC surgery and found that SS31 can significantly improve cardiac function, reduce myocardial interstitial fibrosis, and increase the expression of optic atrophy-associated protein 1 (OPA1), a key protein in mitochondrial fusion. Interestingly, the role of SS31 in improving heart failure and reducing fibrosis is inseparable from the presence of sirtuin3 (Sirt3). We found that in Sirt3KO mice and fibroblasts, the effects of SS31 on improving heart failure and improving fibroblast transdifferentiation were disappeared. Likewise, Sirt3 has direct interactions with proteins critical for mitochondrial fission and fusion. We found that SS31 failed to increase OPA1 expression in both Sirt3KO mice and fibroblasts. Thus, SS31 can alleviate pressure overload-induced heart failure through Sirt3-mediated mitochondrial fusion. This study provides new directions and drug options for the clinical treatment of heart failure caused by pressure overload.

Mitochondria-Targeted Antioxidants as a Therapeutic Strategy for Chronic Obstructive Pulmonary Disease

“…The main advantages of SS peptides over the TPP-like MTAs are that their cellular uptake is energy independent, and their uptake in mitochondria is independent of MMP [ 130 ]. A large body of evidence shows that SS31 treatment reduces ROS production, improves mitochondrial functioning, and prevents mitochondrial structural changes and phospholipid oxidation in different disorders [ 131 , 132 , 133 , 134 ]. SS-31 has also been shown to be safely tolerated and exert protective effects in phase I clinical trials of patients with heart failure [ 135 ] and phase II trials of reperfusion injury patients [ 136 ].…”

Mitochondrial dynamics in vascular remodeling and target-organ damage

“…Interestingly, in a rat model of hypertension with cardiac insufficiency, promoting glucagon-like peptide-1 (GLP-1) production enhanced mitochondrial fusion in the heart and improved cardiac function ( 161 ). In a recent study, the oligopeptide Szeto-Schiller compound 31 (SS31) was found to significantly improve cardiac function, reduce myocardial interstitial fibrosis, and increase expression of optic atrophy-associated protein 1 (Opa1) in mice with pressure-overload heart failure by modulating mitochondrial fusion ( 162 ).…”