Differential effects of low density lipoproteins on insulin-like growth factor-1 (IGF-1) and IGF-1 receptor expression in vascular smooth muscle cells

Low density lipoproteins (LDLs) play an important role in the pathogenesis of atherosclerosis. LDL has been shown to be mitogenic and proapoptotic for vascular smooth muscle cells. However, the mechanisms are poorly understoo d and may result from an alteration in intracellular mitogenic signaling ei ther directly by LDL or indirectly through an autocrine effect involving gr owth factor secretion and/or growth factor receptor expression. Insulin-lik e growth factor-1 (IGF-1) is an autocrine/paracrine factor for vascular smo oth muscle cells and has potent anti-apoptotic effects. Thus, we hypothesiz ed that part of the proliferative responses to LDLs may be explained by its modulation of IGF-1 or IGF-1 receptor (IGF-1R) expression. Treatment of ra t vascular smooth muscle cells with increasing doses of native LDL dose-dep endently increased IGF-1 mRNA by up to 2.6-fold; however, native LDL had no effect on IGF-1R mRNA expression. In contrast, the same doses of oxidized LDL significantly reduced IGF-1 and IGF-1R mRNA by 80 and 61%, respectively , and reduced IGF-1 and IGF-IR protein expression by 63 and 46%. In additio n, native and oxidized LDL significantly increased IGF-l-binding protein-a and IGF l-binding protein-4 expression as measured by Western ligand blot. Most interestingly, anti-IGF-l antiserum completely inhibited LDL-induced b ut not serum-induced increase in H-3-thymidine incorporation, indicating a requirement for IGF-I in the LDL-stimulated mitogenic signaling pathway. In summary, these results suggest that native and oxidized LDLs have differen tial effects on IGF-1 and IGF-1R expression. Because IGF-1 is a potent surv ival factor for vascular smooth muscle cells, our findings suggest that mod erately oxidized LDL may favor proliferation of smooth muscle cells, wherea s oxidized LDL may contribute to plaque apoptosis by local depletion of IGF -I and IGF-1R.