Two peptides LLRLTDL and GYALPCDCL inhibit foam cell formation through activating PPAR‐γ/LXR‐α signaling pathway in oxLDL‐treated RAW264.7 macrophages

Abstract Foam cell formation plays a pivotal role in atherosclerosis‐associated cardiovascular diseases. Bioactive peptides generated from marine sources have been found to provide multifunctional health advantages. In the present study, we investigated the anti‐atherosclerotic effects of LLRLTDL (Bu1) and GYALPCDCL (Bu2) peptides, isolated from ark shell protein hydrolysates by assessing their inhibitory effect on oxidized LDL (oxLDL)‐induced foam cell formation. The two peptides showed a promising anti‐atherosclerotic effect by inhibiting foam cell formation, which was evidenced by inhibiting lipid accumulation in oxLDL‐treated RAW264.7 macrophages and oxLDL‐treated primary human aortic smooth muscle cells (HASMC). Two peptides effectively reduced total cholesterol, free cholesterol, cholesterol ester, and triglyceride levels by upregulating cholesterol efflux and downregulating cholesterol influx. Expression of cholesterol influx‐related proteins such as SR‐A1 and CD36 were reduced, whereas cholesterol efflux‐related proteins such as ATP‐binding cassette transporter ABCA‐1 and ABCG‐1 were highly expressed. In addition, Bu1 and Bu2 peptides increased PPAR‐γ and LXR‐α expression. However, PPAR‐γ siRNA transfection reversed the foam cell formation inhibitory activity of Bu1 and Bu2 peptides. Furthermore, the synergistic effect of Bu1 and Bu2 peptides on foam cell formation inhibition was observed with PPAR‐γ agonist thiazolidinediones, indicating that PPAR‐γ signaling pathway plays a key role in foam cell formation of macrophages. Beyond their impact on foam cell formation, Bu1 and Bu2 peptides demonstrated anti‐inflammatory potential by inhibiting the generation of pro‐inflammatory cytokines and nitric oxide and NF‐κB nuclear activation. Taken together, these results suggest that Bu1 and Bu2 peptides may be useful for atherosclerosis and associated anti‐inflammatory therapies.