PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing the susceptibility for early atherosclerotic lesions in male apolipoprotein E knockout mice
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-athero...
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| Veröffentlicht in: | Atherosclerosis 2021-12, Vol.338, p.23-29 |
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| creator | Zhang, Yiheng Verwilligen, Robin A.F. de Boer, Miriam Sijsenaar, Timothy J.P. Van Eck, Miranda Hoekstra, Menno |
| description | 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.
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.
TP-064 induced a dose-dependent decrease in lipopolysaccharide-induced ex vivo blood monocyte Tnfα secretion (p |
| doi_str_mv | 10.1016/j.atherosclerosis.2021.11.001 |
| format | Article |
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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.
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.
The PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing atherosclerosis susceptibility of male apolipoprotein E knockout mice.
[Display omitted]
•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.]]></description><identifier>ISSN: 0021-9150</identifier><identifier>EISSN: 1879-1484</identifier><identifier>DOI: 10.1016/j.atherosclerosis.2021.11.001</identifier><identifier>PMID: 34785428</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Animals ; Atherosclerosis ; Atherosclerosis - drug therapy ; Atherosclerosis - genetics ; CARM1 ; Cholesterol ; Diet, High-Fat ; Enzyme Inhibitors - pharmacology ; Gene expression ; Liver ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout, ApoE ; Obesity ; PPARgamma ; Protein-Arginine N-Methyltransferases - antagonists & inhibitors</subject><ispartof>Atherosclerosis, 2021-12, Vol.338, p.23-29</ispartof><rights>2021 The Authors</rights><rights>Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c444t-24d260d3277827ee8b2d76d6c1c3d26cfaa9d89b91c1234bb60a4d3bdbbdec753</citedby><cites>FETCH-LOGICAL-c444t-24d260d3277827ee8b2d76d6c1c3d26cfaa9d89b91c1234bb60a4d3bdbbdec753</cites><orcidid>0000-0002-9178-0326 ; 0000-0003-3161-9351 ; 0000-0002-6356-8432 ; 0000-0003-3936-3194</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.atherosclerosis.2021.11.001$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34785428$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Yiheng</creatorcontrib><creatorcontrib>Verwilligen, Robin A.F.</creatorcontrib><creatorcontrib>de Boer, Miriam</creatorcontrib><creatorcontrib>Sijsenaar, Timothy J.P.</creatorcontrib><creatorcontrib>Van Eck, Miranda</creatorcontrib><creatorcontrib>Hoekstra, Menno</creatorcontrib><title>PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing the susceptibility for early atherosclerotic lesions in male apolipoprotein E knockout mice</title><title>Atherosclerosis</title><addtitle>Atherosclerosis</addtitle><description><![CDATA[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.
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.
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.
The PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing atherosclerosis susceptibility of male apolipoprotein E knockout mice.
[Display omitted]
•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.]]></description><subject>Animals</subject><subject>Atherosclerosis</subject><subject>Atherosclerosis - drug therapy</subject><subject>Atherosclerosis - genetics</subject><subject>CARM1</subject><subject>Cholesterol</subject><subject>Diet, High-Fat</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Gene expression</subject><subject>Liver</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout, ApoE</subject><subject>Obesity</subject><subject>PPARgamma</subject><subject>Protein-Arginine N-Methyltransferases - antagonists & inhibitors</subject><issn>0021-9150</issn><issn>1879-1484</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUctuFDEQtBCILIFfQL4gcZnB9nheBw4oCglSEBFazpYfPVlvPONh7AHth_F_6dUGhDhxsaWu6qouFSFvOCs54827fanzDpaYbDi-PpWCCV5yXjLGn5AN79q-4LKTT8mGIVL0vGZn5EVKe8aYbHn3nJxVsu1qKboN-XX79fNWUj_tvPE5LnR7W7AGB-OsbU7UxLxDdAh6HDXiB6onR0fI2sTgLZ2XaCElSPSnz7u4Zmp3errz0x3FM2lak4U5o3bw-UAHNAC9BFT5K0RGnQDJxymhFR11AKpnlJ8jymfA2SW9n6K9P-qP3sJL8mzQIcGrx_-cfPt4ub24Lm6-XH26-HBTWCllLoR0omGuEm3biRagM8K1jWsstxUidtC6d11vem65qKQxDdPSVcYZ48C2dXVO3p508Y7vK6SsRo-BQtATxDUpUfddXbWVlEh9f6JajJUWGNS8-FEvB8WZOjan9uqf5tSxOcW5wuZw__Wj1WpGcH-2f1eFhKsTATDwDw-LStbDZMH5BWxWLvr_tHoAvee5vw</recordid><startdate>202112</startdate><enddate>202112</enddate><creator>Zhang, Yiheng</creator><creator>Verwilligen, Robin A.F.</creator><creator>de Boer, Miriam</creator><creator>Sijsenaar, Timothy J.P.</creator><creator>Van Eck, Miranda</creator><creator>Hoekstra, Menno</creator><general>Elsevier B.V</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-9178-0326</orcidid><orcidid>https://orcid.org/0000-0003-3161-9351</orcidid><orcidid>https://orcid.org/0000-0002-6356-8432</orcidid><orcidid>https://orcid.org/0000-0003-3936-3194</orcidid></search><sort><creationdate>202112</creationdate><title>PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing the susceptibility for early atherosclerotic lesions in male apolipoprotein E knockout mice</title><author>Zhang, Yiheng ; Verwilligen, Robin A.F. ; de Boer, Miriam ; Sijsenaar, Timothy J.P. ; Van Eck, Miranda ; Hoekstra, Menno</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c444t-24d260d3277827ee8b2d76d6c1c3d26cfaa9d89b91c1234bb60a4d3bdbbdec753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Atherosclerosis</topic><topic>Atherosclerosis - drug therapy</topic><topic>Atherosclerosis - genetics</topic><topic>CARM1</topic><topic>Cholesterol</topic><topic>Diet, High-Fat</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Gene expression</topic><topic>Liver</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout, ApoE</topic><topic>Obesity</topic><topic>PPARgamma</topic><topic>Protein-Arginine N-Methyltransferases - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Yiheng</creatorcontrib><creatorcontrib>Verwilligen, Robin A.F.</creatorcontrib><creatorcontrib>de Boer, Miriam</creatorcontrib><creatorcontrib>Sijsenaar, Timothy J.P.</creatorcontrib><creatorcontrib>Van Eck, Miranda</creatorcontrib><creatorcontrib>Hoekstra, Menno</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Atherosclerosis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Yiheng</au><au>Verwilligen, Robin A.F.</au><au>de Boer, Miriam</au><au>Sijsenaar, Timothy J.P.</au><au>Van Eck, Miranda</au><au>Hoekstra, Menno</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing the susceptibility for early atherosclerotic lesions in male apolipoprotein E knockout mice</atitle><jtitle>Atherosclerosis</jtitle><addtitle>Atherosclerosis</addtitle><date>2021-12</date><risdate>2021</risdate><volume>338</volume><spage>23</spage><epage>29</epage><pages>23-29</pages><issn>0021-9150</issn><eissn>1879-1484</eissn><abstract><![CDATA[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.
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.
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.
The PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing atherosclerosis susceptibility of male apolipoprotein E knockout mice.
[Display omitted]
•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.]]></abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>34785428</pmid><doi>10.1016/j.atherosclerosis.2021.11.001</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-9178-0326</orcidid><orcidid>https://orcid.org/0000-0003-3161-9351</orcidid><orcidid>https://orcid.org/0000-0002-6356-8432</orcidid><orcidid>https://orcid.org/0000-0003-3936-3194</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Atherosclerosis Atherosclerosis - drug therapy Atherosclerosis - genetics CARM1 Cholesterol Diet, High-Fat Enzyme Inhibitors - pharmacology Gene expression Liver Male Mice Mice, Inbred C57BL Mice, Knockout, ApoE Obesity PPARgamma Protein-Arginine N-Methyltransferases - antagonists & inhibitors |
| title | PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing the susceptibility for early atherosclerotic lesions in male apolipoprotein E knockout mice |
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