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 SH RSP, the effects of a novel ACAT inhibitor, HL-004, on the accumulatio n and removal of cholesterol were investigated. HL-004 inhibited micro somal 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 2 0 nM, respectively. HL-004 suppressed the accumulation of the intracel lular cholesteryl ester (CE), but did not affect the intracellular fre e cholesterol (FC) content. Removal of cholesterol from the lipid-load ed SMC was accelerated by HL-004. These effects of HL-004 on cholester ol levels showed a good parallel to ACAT inhibition. It would thus app ear that the suppression of cholesterol accumulation and the removal o f cholesterol in SMC by HL-004 can be attributed to its ACAT inhibitio n in the cell, which reduces the content of intracellular CE.