Cardioprotective Potential of a Marine-Derived Tetrapeptide (CAAP) from Paralichthys olivaceus with Dual Antioxidant and ACE-Inhibitory Activities

Excessive lipid peroxidation and renin–angiotensin system dysregulation are central mechanisms linking oxidative stress to hypertension. In this study, a bioactive tetrapeptide, CAAP (Cys-Ala-Ala-Pro), isolated from the muscle hydrolysate of Paralichthys olivaceus (olive flounder), was evaluated for its dual antioxidant and antihypertensive actions. In Vero cells, CAAP significantly suppressed 2,2′-azobis(2-amidinopropane)-induced lipid peroxidation, reduced malondialdehyde accumulation, and preserved cell viability. Fluorescent imaging and flow cytometric analyses revealed that CAAP mitigated nuclear fragmentation and apoptotic sub-G1 cell populations through modulation of the Bcl-xL/Bax/caspase-3 axis, indicating cell protection. Molecular docking analysis demonstrated that CAAP interacts with the S′₂ pocket of angiotensin-converting enzyme (ACE) via hydrogen bonding with Glu281, His513, Lys511, and Tyr520, supporting a strong inhibitory potential (IC₅₀ = 39.3 µg/mL). In spontaneously hypertensive rats, oral administration of CAAP (40 mg/kg) elicited a sustained decrease in systolic blood pressure within 2–6 h post-treatment, comparable to that of captopril. Collectively, these findings highlight CAAP as a multifunctional marine peptide capable of attenuating oxidative and hypertensive injury through cell stabilization and ACE inhibition, suggesting its potential as a natural therapeutic or functional food ingredient for cardiovascular protection.