Identification of a biologically active component in minimally oxidized low density lipoprotein (MM-LDL) responsible for aortic smooth muscle cell proliferation.
Although low concentrations (10 microg/ml) of oxidized LDL density lipoproteins (Ox-LDL) and minimally modified LDL (MM-LDL) can stimulate the proliferation of aortic smooth muscle cells the biologically active component responsible for this phenomena has not been identified. Here we report that the 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-4-phosphocholine (m/e594.3) (POVPC) present in MM-LDL but not 1-palmitoyl-2-glutaryl-sn-glycero-3-phophochline (m/e610.2)(PGPC) can stimulate the activity of UDP-galactose:glucosylceramide (beta 1-->4) galactosyltransferase (GalT-2) and produce lactosyceramide (LacCer). LacCer, in turn, generated superoxide radicals (O(2)(.-)). This is accompanied by the phosphorylation/activation of a cytosolic transcriptional factor p(44) MAPK and the subsequent proliferation of human aortic smooth muscle cells. D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of GalT-2, impaired the induction of GalT-2 activity, O(2)(.-)generation, and cell proliferation. Thus POVPC may serve as a surrogate in MM-LDL mediated induction of aortic smooth muscle cells (A-SMC) proliferation via GalT-2 activation. The LacCer produced as a consequence of GalT-2 activation may serve as a lipid second messenger in the activation of an oxidant sensitive transcriptional pahtway that ultimately leads to cell proliferation and may contribute to the pathophysiology of atherosclerosis.
Chatterjee
Subroto
S
Department of Pediatrics, Lipid Signaling and Vascular Biology Laboratory, Lipid Research-Atherosclerosis Division, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. schatte2@jhmi.edu
Berliner
Judith A
JA
Subbanagounder
Ganesamoorthy G
GG
Bhunia
Anil K
AK
Koh
Steve
S
D001011:Aorta / Q000166:cytology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005700:Galactosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000737:chemistry* / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D010742:Phospholipid Ethers / Q000494:pharmacology; D010743:Phospholipids / Q000494:pharmacology; D010940:Plant Proteins; D013107:Sphingolipids / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
C095823:1-phenyl-2-palmitoylamino-3-morpholino-1-propanol; D008077:Lipoproteins, LDL; D009025:Morpholines; D010742:Phospholipid Ethers; D010743:Phospholipids; D010940:Plant Proteins; D013107:Sphingolipids; C099252:oxidized low density lipoprotein; D013481:Superoxides; D005700:Galactosyltransferases; C063054:galactosylxylosylprotein 3-beta-galactosyltransferase; C101691:MMK4 protein, Medicago sativa; D020928:Mitogen-Activated Protein Kinases