Hyperlipemia and oxidation of LDL induce vascular smooth muscle cell growth: an effect mediated by the HLH factor Id3.
Hyperlipemia and oxidized LDL (ox-LDL) are important independent cardiovascular risk factors. Ox-LDL has been shown to stimulate vascular smooth muscle cell (VSMC) proliferation. However, the effects of hyperlipemia and the molecular mechanisms mediating hyperlipemia and ox-LDL effects on VSMC growth are poorly understood. The helix-loop-helix (HLH) transcription factor, Id3, is a redox-sensitive gene expressed in VSMC in response to mitogen stimulation and vascular injury. Accordingly, we hypothesize that Id3 is an important mediator of ox-LDL and hyperlipemia-induced VSMC growth. Aortas harvested from hyperlipemic pigs demonstrated significantly more Id3 than normolipemic controls. Primary VSMC were stimulated with ox-LDL, native LDL, sera from hyperlipemic pigs, or normolipemic pigs. VSMC exposed to hyperlipemic sera demonstrated increased Id3 expression, VSMC growth and S-phase entry and decreased p21cip1 expression and transcription. Cells stimulated with ox-LDL demonstrated similar findings of increased growth and Id3 expression and decreased p21cip1 expression. Moreover, the effects of ox-LDL on growth were abolished in cells devoid of the Id3 gene. Results provide evidence that the HLH factor Id3 mediates the mitogenic effect of hyperlipemic sera and ox-LDL in VSMC via inhibition of p21cip1 expression, subsequently increasing DNA synthesis and proliferation.
Taylor
Angela M
AM
Department of Internal Medicine, Cardiovascular Division, and the Cardiovascular Research Center, University of Virginia Health System, Charlottesville, VA 22908, USA.
Li
Feng
F
Thimmalapura
Pushpa
P
Gerrity
Ross G
RG
Sarembock
Ian J
IJ
Forrest
Scott
S
Rutherford
Sarah
S
McNamara
Coleen A
CA
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000503:physiopathology*; D051796:Inhibitor of Differentiation Proteins / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D016196:S Phase / Q000502:physiology; D013552:Swine
D050759:Cyclin-Dependent Kinase Inhibitor p21; D051796:Inhibitor of Differentiation Proteins; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein