Key result
Oxidized LDL and hyperlipemic sera drive VSMC growth via Id3 expression.
Why the study?
The effects of hyperlipemia and the molecular mechanisms mediating hyperlipemia and oxidized LDL effects on vascular smooth muscle cell growth are poorly understood.
The HLH factor Id3 mediates the mitogenic effect of hyperlipemic sera and ox-LDL in vascular smooth muscle cells by inhibiting p21cip1 expression, providing a molecular mechanism for hyperlipidemia-induced vascular injury.
Id3 may link hyperlipemia to VSMC proliferation; hypothesis-generating for redox pathways in atherosclerosis, needs prospective validation.
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.
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Taylor et al. (2005) studied Hyperlipemia and vascular smooth muscle cell proliferation. Hyperlipemia and oxidized LDL vs. Normolipemic controls and native LDL was evaluated on Id3 expression, VSMC growth, S-phase entry, and p21cip1 expression. Exposure to hyperlipemic sera and oxidized LDL increased vascular smooth muscle cell growth and Id3 expression, an effect abolished in cells devoid of the Id3 gene.
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