Oxidized low density lipoproteins and lactosylceramide both stimulate the expression of proliferating cell nuclear antigen and the proliferation of aortic smooth muscle cells.
We have previously shown that oxidized low density lipoproteins (Ox-LDL) at low concentrations (10 micrograms/ml) via activating a UDP-galactose: glucosylceramide, beta 1-->4 galactosyl-transferase (GalT-2) and producing lactosylceramide can stimulate the proliferation of aortic smooth muscle cells. In this report, we present evidence that Ox-LDL and LacCer, both can induce the expression of proliferating cell nuclear antigen (cyclin). Ox-LDL and LacCer both exerted a time-dependent stimulation of cyclin expression. Maximum increase (3-fold) in cyclin expression occurred between 30-120 min after Ox-LDL/LacCer addition and decreased thereafter. D-threo-l-phenyldecanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of GalT-2, inhibited cell proliferation as well as cyclin expression. This inhibitor also abrogated the Ox-LDL mediated expression of proliferating cell nuclear antigen (cyclin). In contrast, the L-enantiomer of PDMP (L-PDMP) stimulated the expression of cyclin and augmented the Ox-LDL mediated expression of cyclin in these cells. Maximum increase in the expression of cyclin occurred with 20 mumole of L-PDMP and 10 micrograms of Ox-LDL. This overall pattern of Ox-LDL and LacCer mediated regulation is similar to that of the c-fos protooncogenes reported previously by us. We hypothesize that the early induction of GalT-2 may serve as an "Immediate early gene" that plays a role in the signalling cascade by LacCer and involves the kinase c-fos induction and subsequent expression of cyclins. Thus, GalT-2 may play a role in the proliferative response in aortic smooth muscle cells by Ox-LDL.
Chatterjee
S
S
Dept. of Pediatrics, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21287-3654, USA.
D000818:Animals; D015703:Antigens, CD; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005700:Galactosyltransferases / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007790:Lactosylceramides / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D011817:Rabbits
D015703:Antigens, CD; D004791:Enzyme Inhibitors; D007790:Lactosylceramides; D008077:Lipoproteins, LDL; D009025:Morpholines; D018809:Proliferating Cell Nuclear Antigen; C099252:oxidized low density lipoprotein; C009744:CDw17 antigen; C033110:RV 538; D005700:Galactosyltransferases