title: Effects of HL-004, a novel ACAT inhibitor, on cholesterol accumulation and removal in cultured smooth muscle cells from stroke-prone spontaneously hypertensive rats (SHRSP).
abstract: The cholesterol metabolism of cultured smooth muscle cells (SMC) from the thoracic aorta of SMC from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) was compared. SMC from SHRSP had a higher acylCoA:cholesterol acyltransferase (ACAT) activity and accumulated more cholesterol than those from WKY. By using SMC from SHRSP, the effects of a novel ACAT inhibitor, HL-004, on the accumulation and removal of cholesterol were investigated. HL-004 inhibited microsomal ACAT activity from rabbit liver, intestine, aorta, and cultured SMC of SHRSP with 50% inhibition (IC50) values of 2.2, 1.7, 7.9, and 20 nM, respectively. HL-004 suppressed the accumulation of the intracellular cholesteryl ester (CE), but did not affect the intracellular free cholesterol (FC) content. Removal of cholesterol from the lipid-loaded SMC was accelerated by HL-004. These effects of HL-004 on cholesterol levels showed a good parallel to ACAT inhibition. It would thus appear that the suppression of cholesterol accumulation and the removal of cholesterol in SMC by HL-004 can be attributed to its ACAT inhibition in the cell, which reduces the content of intracellular CE.
authors.affiliation: Research Center, Taisho Pharmaceutical Co. Ltd., Ohmiya, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Murakami
authors.forename: H
authors.initials: H
authors.lastname: Araki
authors.forename: S
authors.initials: S
authors.lastname: Otomo
authors.forename: Y
authors.initials: Y
authors.lastname: Nara
authors.forename: Y
authors.initials: Y
authors.lastname: Yamori
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000502:physiology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
chemical_list: D000083:Acetanilides; C092284:HL 004; D008075:Lipoproteins, HDL; D002784:Cholesterol; D002785:Sterol O-Acyltransferase