Role of cholesterol ester pathway in the control of cell cycle in human aortic smooth muscle cells.
Cholesterol esterification by acyl-CoA:cholesterol acyltransferase (ACAT) and proliferation of vascular smooth muscle cells (VSMC) are key events in vascular proliferative diseases. Here we performed experiments to ascertain the role of cholesterol ester pathway in the control of human aortic VSMC cycle progression. Results showed that serum-induced VSMC proliferation was preceded by an increased ability of the cells to esterify cholesterol as well as by an increased expression of ACAT and multidrug resistance (MDR1) mRNAs and extracellular related kinases 1/2 (ERK1/2), whereas caveolin-1 levels were markedly decreased. Cell cycle analyses performed in the presence of two inhibitors of cholesterol esterification, directly inhibiting ACAT (Sandoz 58-035) or the transport of cholesterol substrate from plasma membrane to endoplasmic reticulum (progesterone), indicate that each inhibitor suppressed the serum-induced DNA synthesis by accumulation of VSMCs in the G1 phase. The effect was associated with a rapid inhibition of ERK1/2 mitogenic signaling pathway; a down-regulation of cyclin D1, ACAT, and MDR1 mRNA; and an up-regulation of caveolin-1. These data provide a plausible link between cholesterol esterification and control of cell cycle G1/S transition, supporting the hypothesis that cholesterol esterification may accelerate the progression of human vascular proliferative diseases by modulating the rate of the VSMC proliferation.
Batetta
Barbara
B
Department of Biomedical Science and Biotechnology, University of Cagliari, Italy.
Mulas
Maria F
MF
Sanna
Francesca
F
Putzolu
Marirosa
M
Bonatesta
Rosa R
RR
Gasperi-Campani
Anna
A
Roncuzzi
Laura
L
Baiocchi
Daniela
D
Dessì
Sandra
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000577:Amides / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051242:Caveolin 1; D022461:Caveolins / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017646:Organosilicon Compounds / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D002785:Sterol O-Acyltransferase / Q000235:genetics; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000577:Amides; C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D002788:Cholesterol Esters; D017646:Organosilicon Compounds; D012333:RNA, Messenger; D011374:Progesterone; C040256:SAN 58035; D002784:Cholesterol; D002785:Sterol O-Acyltransferase