Amelioration of obesity-induced endothelial dysfunction by a synthetic ocean-derived peptide via regulating PPARα/γ pathway

Emerging biosynthetic strategies enable precision engineering of bioactive peptides with vasoprotective properties, positioning them as promising therapeutics for vasculopathy. In this study, a synthetic ocean-derived peptide (SOP) was designed, mimicking the most potent antioxidant peptide found in natural oyster, exhibiting radical scavenging capacity equivalent to 2.16 mM vitamin C. The efficacy of SOP in ameliorating aortic endothelial dysfunction was subsequently evaluated in vitro and in vivo. Our findings revealed that SOP administration in obese mice led to marked improvements in key metabolic parameters, including serum levels of total Cholesterol (TC), triglycerides (TG) and fasting blood glucose (FBG), along with a reduction in blood pressure. This was accompanied by a pronounced restoration of endothelium-dependent relaxation (EDR) in the aorta. Mechanistically, SOP upregulated the protein expression of Peroxisome Proliferator-activated Receptor alpha/gamma (PPARα/γ), heme oxygenase-1 (HO-1) and phosphorylated endothelial nitric oxide synthase (p-eNOS) in both mouse aortas and primary rat aortic endothelial cells (RAECs). Furthermore, SOP alleviated oxidative stress by reducing Reactive Oxygen Species (ROS) production and preserving nitric oxide (NO) bioavailability. Crucially, these positive actions were attenuated by PPARα Antagonist GW6471, which concurrently exacerbated oxidative stress. Collectively, these findings demonstrate that SOP confers protection against obesity-induced aortic dysfunction, primarily through the PPARα/γ signaling pathway.