Effects of 26-aminocholesterol, 27-hydroxycholesterol, and 25-hydroxycholesterol on proliferation and cholesterol homeostasis in arterial myocytes.
The major relation existing between cell growth and cholesterol homeostasis prompted us to investigate the effect of 26-aminocholesterol (26-NH2), 27-hydroxycholesterol (27-OH), and 25-hydroxycholesterol (25-OH) on these cellular events. To test this relation, we incubated human and rat arterial myocytes with the sterols for 72 hours. All the tested compounds (0.5 to 7.5 mumol/L) inhibited rat and human myocyte proliferation and cholesterol biosynthesis in a dose-dependent manner. 26-NH2 was more potent than oxysterols in inhibiting human myocyte proliferation but equieffective in rat cells; 27-OH and 25-OH displayed similar activity in both cell lines. Inhibition of nuclear incorporation of thymidine in rat myocytes is consistent with decreased cell count. The antiproliferative effect of the tested sterols was reversible. The high inhibition (80%) of cholesterol biosynthesis necessary to induce a decrease in myocyte proliferation suggests a causal relation between the cholesterol synthetic pathway and these cellular processes. In addition, all the tested sterols were able to inhibit hydroxymethyl glutaryl-coenzyme A reductase activity in intact myocytes but not in cell-free extracts. The finding that 26-NH2 but not 27-OH or 25-OH does not suppress LDL receptor activity in either human or rat myocytes supports the achievement of selectivity over the coordinately regulated LDL receptor gene. The ability of 26-NH2 to interfere with myocyte proliferation and cholesterol synthesis without affecting the LDL receptor pathway confers at least in vitro a pharmacological interest on the compound in the process of atherogenesis.
Corsini
A
A
Institute of Pharmacological Sciences, University of Milan, Italy.
Verri
D
D
Raiteri
M
M
Quarato
P
P
Paoletti
R
R
Fumagalli
R
R
D000818:Animals; D001158:Arteries / Q000166:cytology / Q000378:metabolism*; D002455:Cell Division; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D006706:Homeostasis; D006888:Hydroxycholesterols / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000502:physiology
D006888:Hydroxycholesterols; D008074:Lipoproteins; D011973:Receptors, LDL; C076996:27-hydroxycholesterol; C058194:26-aminocholesterol; C007997:25-hydroxycholesterol; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases