Do oxidized polyunsaturated Fatty acids affect endoplasmic reticulum stress-induced apoptosis in human carotid plaques?

Macrophage apoptosis is involved in atherosclerotic plaque development. The aim of this study was to evaluate the interrelationship between macrophage apoptosis and the endoplasmic reticulum (ER) stress in the tissue around the necrotic core (TANC) and in the periphery (P) of the same carotid plaques derived from patients undergoing carotid endarterectomy. Apoptosis was significantly higher in TANC than in P (p<0.001). mRNA and protein expression of the protein kinase-like ER kinase (Perk) and the nuclear erythroid-related factor 2 (Nrf2)-related survival genes was significantly higher in P than in TANC (p<0.01), while CCAAT/enhancer-binding protein homologous protein (Chop) and the apoptosis-related genes were higher in TANC than in P (p<0.01). The TANC extract was characterized by significantly higher concentrations of oxidized derivatives of polyunsaturated fatty acids (PUFAs) than the P extract (p<0.01). When THP-1 cells were incubated with P or TANC extracts there was a dose-dependent increase of Perk and Nrf2 or of Chop and of the apoptosis-related genes, respectively (p<0.01). Our observations lead to the hypothesis that ER stress induced by oxidized derivatives of PUFAs may promote macrophage apoptosis in TANC and favor the expansion of the necrotic core of the plaques, a major feature responsible for its disruption and acute luminal thrombosis.