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).

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.