Abstract
Background and aimsAtherosclerotic cardiovascular disease is a metabolic and inflammatory disorder. In vitro studies have suggested that protein arginine methyltransferase 4 (PRMT4) may act as a transcriptional coactivator to modulate inflammatory and metabolic processes. Here we investigated the potential anti-atherogenic effect of PRMT4 inhibitor TP-064 in vivo. MethodsMale apolipoprotein E knockout mice fed a high cholesterol/high fat Western-type diet were intraperitoneally injected three times a week with 2.5 mg/kg (low dose) or 10 mg/kg (high dose) TP-064 or with DMSO control. ResultsTP-064 induced a dose-dependent decrease in lipopolysaccharide-induced ex vivo blood monocyte Tnfα secretion (p < 0.05 for trend) in the context of unchanged blood monocyte concentrations and neutrophilia induction (p < 0.01 for trend). A dose-dependent decrease in gonadal white adipose tissue expression levels of PPARγ target genes was detected, which translated into a reduced body weight gain after high dose TP-064 treatment (p < 0.05). TP-064 treatment also dose-dependently downregulated gene expression of the glycogen metabolism related protein G6pc in the liver (p < 0.001 for trend). In addition, a trend towards lower plasma insulin and higher blood glucose levels was observed, which was paralleled by a reduction in hepatic mRNA expression levels of the insulin-responsive genes Fasn (−55%; p < 0.001) and Gck (−47%; p < 0.001) in high dose-treated mice. Plasma triglyceride levels were reduced by high dose TP-064 treatment (−30%; p < 0.05). However, no change was observed in the size or composition of aortic root atherosclerotic lesions. ConclusionsThe PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing atherosclerosis susceptibility of male apolipoprotein E knockout mice.
Highlights
Atherosclerosis, the primary underlying cause of cardiovascular disease, is a chronic inflammatory disease characterized by the accu mulation of lipids and inflammatory monocyte-derived macrophages within the arterial wall [1]
In line with our previous finding that TP-064 at a dosage of 10 mg/kg bodyweight promotes neutrophilia in wild-type mice due to its nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) inhibitory action [8], we observed that TP-064 induced a significant increase of neutrophil numbers in high dose-treated mice
The TP-064-induced neutrophilia did not translate into any changes in plasma concentrations of the pro-inflammatory mediators monocyte chemoattractant protein-1 (Mcp-1) and serum amyloid P component (SAP) (Fig. 1B)
Summary
Atherosclerosis, the primary underlying cause of cardiovascular disease, is a chronic inflammatory disease characterized by the accu mulation of lipids and inflammatory monocyte-derived macrophages within the arterial wall [1]. PRMT4 belongs to the PRMT family of enzymes that methylate arginine residues to generate asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) [2,3,4] Through this methylating action, PRMTs can influence a variety of cellular activities, i.e., they regulate cell proliferation and modulate transcription by acting as coactivators/corepressors [5]. TP-064 treatment dose-dependently downregulated gene expression of the glycogen metabolism related protein G6pc in the liver (p < 0.001 for trend). A trend towards lower plasma insulin and higher blood glucose levels was observed, which was paralleled by a reduction in hepatic mRNA expression levels of the insulin-responsive genes Fasn (− 55%; p < 0.001) and Gck (− 47%; p < 0.001) in high dose-treated mice. Conclusions: The PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing atherosclerosis susceptibility of male apolipoprotein E knockout mice
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