Haloperidol inhibits the development of atherosclerotic lesions in LDL receptor knockout mice

Autor:	Menno Hoekstra, Ronald J. van der Sluis, Miranda Van Eck, Joya E. Nahon, Anne Q Reuwer
Rok vydání:	2015
Předmět:	Pharmacology medicine.medical_specialty Cholesterol Reverse cholesterol transport Biology Cholesterol 7 alpha-hydroxylase Macrophage chemotaxis chemistry.chemical_compound Endocrinology chemistry Internal medicine ABCA1 LDL receptor medicine biology.protein Haloperidol lipids (amino acids peptides and proteins) Lipoprotein medicine.drug
Zdroj:	British Journal of Pharmacology. 172:2397-2405
ISSN:	0007-1188
Popis:	Background and Purpose Antipsychotic drugs have been shown to modulate the expression of ATP-binding cassette transporter A1 (ABCA1), a key factor in the anti-atherogenic reverse cholesterol transport process, in vitro. Here we evaluated the potential of the typical antipsychotic drug haloperidol to modulate the cholesterol efflux function of macrophages in vitro and their susceptibility to atherosclerosis in vivo. Experimental Approach Thioglycollate-elicited peritoneal macrophages were used for in vitro studies. Hyperlipidaemic low-density lipoprotein (LDL) receptor knockout mice were implanted with a haloperidol-containing pellet and subsequently fed a Western-type diet for 5 weeks to induce the development of atherosclerotic lesions in vivo. Key Results Haloperidol induced a 54% decrease in the mRNA expression of ABCA1 in peritoneal macrophages. This coincided with a 30% decrease in the capacity of macrophages to efflux cholesterol to apolipoprotein A1. Haloperidol treatment stimulated the expression of ABCA1 (+51%) and other genes involved in reverse cholesterol transport, that is, CYP7A1 (+98%) in livers of LDL receptor knockout mice. No change in splenic ABCA1 expression was noted. However, the average size of the atherosclerotic size was significantly smaller (−31%) in the context of a mildly more atherogenic metabolic phenotype upon haloperidol treatment. More importantly, haloperidol markedly lowered MCP-1 expression (−70%) and secretion (−28%) by peritoneal macrophages. Conclusions and Implications Haloperidol treatment lowered the susceptibility of hyperlipidaemic LDL receptor knockout mice to develop atherosclerotic lesions. Our findings suggest that the beneficial effect of haloperidol on atherosclerosis susceptibility can be attributed to its ability to inhibit macrophage chemotaxis.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::d8e5fd146eda770992201fff2c9b4f0f https://doi.org/10.1111/bph.13067 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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