2-(2-Phenylethyl)chromone-enriched extract of Chinese agarwood (Aquilaria sinensis) inhibits atherosclerosis progression through endoplasmic reticulum stress-mediated CD36 expression in macrophages

Chinese agarwood, derived from the Aquilaria sinensis (Lour.) Gilg (Thymelaeaceae), has a long history of use in Traditional Chinese Medicine for the management of cardiovascular disease. However, the specific active ingredients responsible for its impact on atherosclerosis are yet to be fully understood. Aim of the study: The aim of this study is to investigate the anti-atherosclerotic effectiveness of the 2-(2-phenylethyl)chromone-enriched extract derived from Chinese agarwood (CPE) through the ER stress-mediated CD36 pathway. To assess the effectiveness of CPE, an atherosclerotic mouse model was established using ApoE−/− mice with a high-fat diet. Then we assessed the impact of CPE on lipid accumulation in THP-1 macrophages that were exposed to oxLDL. Subsequently, the effect of CPE on the expression of CD36 and markers related to ER stress was characterized. Our in vivo research confirmed that CPE effectively reduces the formation of aortic plaques in atherosclerotic ApoE−/− mice. Additionally, our in vitro study observed that CPE inhibits the uptake of oxLDL and hinders the generation of foam cells. This effect is achieved by downregulating the level of CD36 in macrophages. Furthermore, our study revealed that the increase in CD36 expression, resulting from oxLDL exposure, is governed by the activation of JNK1/2/3 signaling pathways and the initiation of ER stress. CPE demonstrated significant efficacy to inhibit the atherosclerosis. The ER stress/P-JNK/PPARγ/CD36 signaling pathway plays critical involvement in modulating the foam cell formation in vitro and in vivo. These findings underscore the efficacy of CPE as a viable therapeutic intervention for the treatment of atherosclerosis.