Background
Asprosin, a newly discovered adipokine, is a C-terminal cleavage product of profibrillin. Asprosin has been reported to participate in lipid metabolism and cardiovascular disease, but its role in atherogenesis remains elusive.
Methods
Asprosin was overexpressed in THP-1 macrophage-derived foam cells and apoE−/− mice using the lentiviral vector. The expression of relevant molecules was determined by qRT-PCR and/or western blot. The intracellular lipid accumulation was evaluated by high-performance liquid chromatography and Oil red O staining. HE and Oil red O staining was employed to assess plaque burden in vivo. Reverse cholesterol transport (RCT) efficiency was measured using [3H]-labeled cholesterol.
Results
Exposure of THP-1 macrophages to oxidized low-density lipoprotein down-regulated asprosin expression. Lentivirus-mediated overexpression of asprosin promoted cholesterol efflux and inhibited lipid accumulation in THP-1 macrophage-derived foam cells. Mechanistic analysis revealed that asprosin overexpression activated p38 and stimulated the phosphorylation of ETS-like transcription factor (Elk-1) at Ser383, leading to Elk-1 nuclear translocation and the transcriptional activation of ATP binding cassette transporters A1 (ABCA1) and ABCG1. Injection of lentiviral vector expressing asprosin diminished atherosclerotic lesion area, increased plaque stability, improved plasma lipid profiles and facilitated RCT in apoE−/− mice. Asprosin overexpression also increased the phosphorylation of p38 and Elk-1 as well as up-regulated the expression of ABCA1 and ABCG1 in the aortas.
Conclusion
Asprosin inhibits lipid accumulation in macrophages and decreases atherosclerotic burden in apoE−/− mice by up-regulating ABCA1 and ABCG1 expression via activation of the p38/Elk-1 signaling pathway.
Doxorubicin (Dox) is identified as a broad-spectrum and efficient chemotherapeutic agent for multiple human solid and hematopoietic cancers; however, adverse cardiovascular events due to the cumulative cardiotoxicity extremely impede its clinical use. [1][2][3] Despite the exact mechanisms of Dox-induced cardiotoxicity remain unclear, reactive oxygen species (ROS) overproduction and oxidative damage are implicated in the pathogenesis of Doxinduced cardiotoxicity. 4,5 Zhang et al. 6 previously has revealed that Dox forms a ternary cleavage complex with topoisomerase-II beta and DNA, which subsequently destroys the structure and function of mitochondria, and leads to excessive ROS generation. In addition, Dox treatment can increase the accumulation of iron inside the mitochondria, and then promote ROS amplification through a Fenton reaction. 7 Moreover, the heart is especially vulnerable to oxidative damage due to the less active antioxidant defence and negligible regenerative capability. 8 Accordingly, our recent study demonstrated that inhibiting oxidative stress significantly prevented Dox-induced cardiotoxicity and dysfunction. 9 Therefore, it is reasonable to treat Dox-induced cardiotoxicity through inhibiting oxidative stress.
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