Role of simvastatin and RORα activity in the macrophage apoptotic pathway

Abstract

Objective: Atherosclerosis is a chronic inflammatory condition and is one of the main causes of death worldwide. Macrophages play important roles in the formation of atherosclerotic plaques. Apoptosis is progressively observed while plaques develop, although the precise mechanisms and outcomes of apoptosis in atherosclerosis development and progression are still contradictory. This study was conducted to explore the effects of simvastatin and retinoic acid receptor-related orphan receptor alpha (RORa) ligands on apoptosis in human acute monocytic leukemia (THP-1) macrophage cells. Methods: Briefly, the occupancy of RORa in the promoter regions of apoptotic pathway genes was demonstrated in THP-1 cell lines using chromatin immunoprecipitation (ChIP) analysis. In order to modulate RORa activity, THP-1 macrophage cells were treated with specific ligands (CPG52608 and SR1001) and then viability as well as count of THP-1 macrophage cells were analyzed. Results: We observed that simvastatin and both RORa ligands had a tendency to decrease THP-1 macrophage cell viability in culture. When compared with non-treated controls, simvastatin significantly decreased cell viability (p=0.04) and cell count (p=0.03). However, this negative effect of simvastatin seemed to be partly prevented by RORa ligands. In addition, bioinformatics analysis of ChIP-on-chip data demonstrated that several genes that are involved in the apoptotic pathway were likely RORa target genes. These genes were involved in the regulation of apoptosis through various pathways. Conclusion: In summary, our study suggest that simvastatin-mediated macrophage apoptosis might be modulated by SR1001 administration. However, involvement of RORa in this modulation through potential apoptotic target genes remains elusive.

Simvastatin Impairs the Inflammatory and Repair Phases of the Postinjury Skeletal Muscle Regeneration

“…This increased inflammation after SIM therapy that was observed starting from day 3 in the BPVC-injured muscles provided evidence that SIM did not exert an anti-inflammatory effect in the postinjury skeletal muscle regeneration. This conclusion is not in agreement with previous studies that revealed the ability of statins to decrease the recruitment of neutrophils and macrophages under many conditions [ 8 – 10 , 29 ]. Furthermore, as observed in the SIM-treated group, a persistently high level of inflammation should accelerate the removal of cellular debris, reduce the necrosis duration, and positively affect regeneration, but these effects were not observed in the present study.…”

“…This conclusion is supported by previous studies indicating that statins inhibit the secretory activity of neutrophils and macrophages and regulate the expression of factors and molecules that control their phagocytic action [ 10 , 30 , 31 ]. Moreover, the improper phagocytic activity of inflammatory cells detected after SIM treatment could also be the result of increased apoptosis of neutrophils and macrophages, as suggested by other investigators [ 9 , 29 ] and will be the subject of further research. Furthermore, taking into account the results of the present study and the fact that M1 and M2 macrophage activity occurs starting on day 3 of the postinjury skeletal muscle regeneration, it should be assumed that SIM affects these inflammatory cells rather than neutrophils.…”

Hypolipidemic and anti‐inflammatory effects of aorta and heart tissues of cattle and pigs in the atherosclerosis rat model

“…Atherosclerosis is the major risk factor for cardiovascular disease, and the number of deaths from this disease is increasing every year; therefore, the prevention of atherosclerosis and cardiovascular disease is quite an important problem (Çoban et al . ). Lifestyle‐related diseases such as obesity, hypertension, diabetes mellitus and disorders of lipid metabolism potentially cause atherosclerosis.…”

Induction of apoptosis in RL95-2 human endometrial cancer cells by combination treatment with docosahexaenoic acid and triacsin C

“…Studies with triacsin C have shown that inhibiting ACS leads to apoptosis in human T lymphoblastoma [ 26 ], glioma [ 27 , 28 ], and hepatocellular carcinoma cells [ 29 ] through pathways mediated by mitochondria. Another study showed that treatment with simvastatin, a lipid-lowering drug, decreases proliferation of human acute monocytic leukaemia (THP-1) macrophage cells [ 30 ]. Based on these findings, it has been hypothesised that the inhibition of ACS by triacsin C would impair DHA metabolism, which contributes to cytotoxicity-induced apoptosis by DHA in RL95-2 endometrial carcinoma.…”