title: Cooperation between low density lipoproteins and IGF-I in the promotion of mitogenesis in vascular smooth muscle cells.
abstract: Low density lipoproteins (LDL) are an independent risk factor for atherosclerosis and show synergism with some growth factors in vascular smooth muscle cell (VSMC) proliferation. IGF-I has mitogenic actions on VSMC, which, in turn, show enhanced expression of IGF-I and its receptor when exposed to hypercholesterolemic diets in vivo. To investigate the molecular basis of a possible interaction between LDL and the IGF-I signaling system in VSMC, we used A10 cells, where synergism between both factors in DNA synthesis was demonstrated. IGF-I activates phosphatidylinositol 3-kinase (PI3 kinase) and extracellular signal-regulated MAPK pathways in A10 cells, although insulin receptor substrate-1 (IRS-1)-associated PI3 kinase is more closely linked to IGF-I induced proliferation. LDL, in pathophysiological concentrations, affect the IGF-I signaling pathway at multiple levels: 1) they induce phosphorylation of IGF-I receptor beta and IRS-1 in a time- and dose-dependent manner; 2) they up-regulate IRS-1-associated PI3 kinase/Akt activation in response to IGF-I at early times; and 3) they show additive effects with IGF-I on extracellular signal-regulated MAPK 1/2 phosphorylation. These actions are not present in very low density lipoprotein treatments. Taken together, these results indicate specific cooperation between LDL and the IGF-I signaling pathways and may represent a more general mechanism through which proatherogenic lipoproteins modulate VSMC response to growth factors.
authors.affiliation: Endocrinology Division, Hospital Carlos III, Instituto de Salud Carlos III, Madrid 28029, Spain.
authors.forename: B
authors.initials: B
authors.lastname: González
authors.forename: S
authors.initials: S
authors.lastname: Lamas
authors.forename: E M
authors.initials: EM
authors.lastname: Melián
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004357:Drug Synergism; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000494:pharmacology / Q000502:physiology*; D008938:Mitosis / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D008077:Lipoproteins, LDL; D010750:Phosphoproteins; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1