Abstract
Atherosclerosis is the major worldwide cause of mortality for patients with coronary heart disease. Many traditional Chinese medicine compound prescriptions for atherosclerosis treatment have been tried in patients. Dan-Lou prescription, which is improved from Gualou-Xiebai-Banxia decoction, has been used to treat chest discomfort (coronary atherosclerosis) for approximately 2,000 years in China. Although the anti-inflammatory activities of Dan-Lou prescription have been proposed previously, the mechanism remains to be explored. Based on the interaction between inflammation and atherosclerosis, we further investigated the effect of Dan-Lou prescription on macrophage-derived foam cell formation and disclosed the underlying mechanisms. In the oxidative low-density lipoprotein (ox-LDL) induced foam cells model using murine macrophage RAW 264.7 cells, the ethanol extract from Dan-Lou prescription (EEDL) reduced ox-LDL uptake and lipid deposition by inhibiting the protein and mRNA expression of Toll-like receptor (TLR)4 and scavenger receptor (SR)B1. After stimulation with ox-LDL, the metabolic profile of macrophages was also changed, while the intervention of the EEDL mainly regulated the metabolism of isovalerylcarnitine, arachidonic acid, cholesterol, aspartic acid, arginine, lysine, L-glutamine and phosphatidylethanolamine (36:3), which participated in the regulation of the inflammatory response, lipid accumulation and cell apoptosis. In total, 27 inflammation-related gene targets were screened, and the biological mechanisms, pathways and biological functions of the EEDL on macrophage-derived foam cells were systemically analyzed by Ingenuity Pathway Analysis system (IPA). After verification, we found that EEDL alleviated ox-LDL induced macrophage foam cell formation by antagonizing the mRNA and protein over-expression of PPARγ, blocking the phosphorylation of IKKα/β, IκBα and NF-κB p65 and maintaining the expression balance between Bax and Bcl-2. In conclusion, we provided evidences that Dan-Lou prescription effectively attenuated macrophage foam cell formation via the TLR4/NF-κB and PPARγ signaling pathways.
Highlights
Atherosclerosis is the major cause of mortality for patients with coronary heart disease worldwide
We aimed to investigate how ethanol extract from Dan-Lou prescription (EEDL) protected cells from ox-LDLinduced macrophage foam cell formation, and to elucidate the underlying mechanism
We investigated the anti-apoptotic effect of the EEDL on oxidative low-density lipoprotein (ox-lowdensity lipoprotein (LDL)) induced macrophage foam cells
Summary
Atherosclerosis is the major cause of mortality for patients with coronary heart disease worldwide It is characterized by complex interactions, including lipid deposition, vascular smooth muscle cell proliferation, endothelial dysfunction and extracellular matrix remodeling (Lim and Park, 2014). Since the 1800s, the concept of atherosclerosis related to inflammation has been reported (Wong et al, 2012). Until the 2000s, more and more researchers have appreciate that inflammatory mechanisms couple dyslipidemia to atheroma formation (Libby, 2002). The “inflammation hypothesis” is further strongly acknowledged combining the detection of circulating inflammatory markers in patients and possibility of selective gene modification in mice (Libby et al, 2002). The therapeutic strategies for attenuating inflammation have been the focus of multiple clinical trials and most anti-inflammatory therapies used in phase II and III trials show promising results (Al-Hawwas and Tanguay, 2013)
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