Mitochondria-Targeting Peptide SS-31 Prevents Atherosclerosis Development in Mice

Chronic subcutaneous administration of the mitochondria-targeted peptide SS-31 at 1 mg/kg/day and 3 mg/kg/day for 12 weeks reduced atherosclerotic plaque area and size in ApoE knockout mice fed a Western diet. SS-31 suppressed oxidative stress (reduced DHE staining, lower 8-OHDG, increased SOD activity), reduced systemic inflammation (decreased ICAM-1, MCP-1, and IL-6 levels), and inhibited cholesterol influx by downregulating CD36 and LOX-1 expression, preventing foam cell formation. Plaque composition also changed, suggesting more stable plaques.

Male ApoE knockout mice (8 weeks old) were fed a Western diet and received daily subcutaneous injections of either saline (control) or SS-31 (1 mg/kg/d or 3 mg/kg/d) for 12 weeks. Atherosclerotic plaques were assessed by Oil Red O staining. Oxidative stress was measured by DHE staining and 8-OHDG immunohistochemistry. ATP levels, SOD activity, inflammatory markers (ICAM-1, MCP-1, IL-6, CRP), cholesterol transport receptors (CD36, LOX-1, ABCA1), and plaque composition (CD68, α-SMA, Masson's trichrome) were analyzed.

Atherosclerosis is the leading cause of heart attacks and strokes, and current treatments primarily manage cholesterol levels and symptoms rather than directly targeting the oxidative stress and mitochondrial dysfunction that drive plaque formation. SS-31 (also known as elamipretide) targets the root cause — mitochondrial dysfunction — by binding cardiolipin in the inner mitochondrial membrane. This study suggests that protecting mitochondrial function could be a novel therapeutic strategy for preventing cardiovascular disease.

SS-31 (elamipretide) is one of the most studied mitochondria-targeted peptides, with research spanning heart failure, kidney disease, neurodegenerative disorders, and aging. This study extends its potential to atherosclerosis prevention, reinforcing the idea that mitochondrial dysfunction is a unifying mechanism across many age-related diseases. If these results translate to humans, mitochondria-targeted peptides could represent an entirely new class of cardiovascular preventive therapy.

This is a mouse study using a genetic model of atherosclerosis (ApoE knockout) that does not perfectly replicate human cardiovascular disease. The ApoE knockout model develops much more aggressive atherosclerosis than typically occurs in humans. Specific quantitative results (percentage reductions in plaque area, inflammation markers) are not provided in the abstract. Long-term safety of chronic SS-31 administration was not assessed.