PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing the susceptibility for early atherosclerotic lesions in male apolipoprotein E knockout mice. (December 2021)

• Record Type: Journal Article
• Authors: Zhang, Yiheng; Verwilligen, Robin A.F.; de Boer, Miriam; Sijsenaar, Timothy J.P.; Van Eck, Miranda; Hoekstra, Menno
• Is Part Of: Atherosclerosis. Volume 338(2021)
• Page Start: 23
• Page End: 29
• Publication Date: 2021-12
• Subjects: Gene expression -- CARM1 -- Atherosclerosis -- Obesity -- PPARgamma; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2021.11.001
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Atherosclerotic 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 . Methods: Male 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. Results: TP-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. Conclusions: The PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing atherosclerosis susceptibility of male apolipoprotein E knockout mice. Graphical abstract: Image 1 Highlights: Protein arginine methyltransferase 4 (PRMT4) is overexpressed in white blood cells of atherosclerotic patients. TP-064 dose-dependently downregulates PRMT4-mediated transcription in vivo . Chronic TP-064 treatment does not change atherosclerosis susceptibility. PRMT4 can possibly serve as novel therapeutic target in obesity.