Abstract 420: Stearoyl-coa Desaturase-1 Protects Against Saturated Fatty Acids-Induced Osteogenic Differentiation and Apoptosis of Vascular Smooth Muscle Cells
Elevated plasma concentrations of free fatty acids (FFA) are a significant risk factor for the development of vascular disease in the patients with dyslipidemia of insulin resistance and type 2 diabetes. Stearoyl-coenzyme A desaturase 1 (SCD1) is a central lipogenic enzyme that catalyzes the synthesis of monounsaturated fatty acids from saturated fatty acids and has emerged as a key regulator of metabolism. However, little is known about the role of SCD1 in vascular calcification characterizing diabetic vasculopathy. Here we examined the effects of the components of FFA and SCD1 on osteogenic gene expression in vascular smooth muscle cells. Cultured human aortic smooth muscle cells (HASMCs) were stimulated with saturated fatty acids, such as palmitic acid and stearic acid, and monounsaturated fatty acid, oleic acid. Real time-PCR analyses showed that palmitic acid (250μM) and stearic acid (250μM) but not oleic acid (250μM) significantly induced the battery of osteogenic genes such as bone morphogenetic protein-2 (BMP-2), Runx2/Cbfa1, Msx2 and osteopontin (3.3 ± 0.5*, 2.4 ± 0.4*, 4.0 ± 0.6*, 4.6 ± 0.4 fold*, relative to control, respectively, *p<0.01). Such an increase was inhibited by PKC inhibitor but not by MAP kinase inhibitor or PI-3 kinase inhibitor. Furthermore, stimulation with either palmitic acid - or stearic acid induced apoptosis in HASMC as determined by caspase-3 activity and TUNEL staining (1.9 ± 0.2*, 5.3 ± 0.6 fold*, relative to control, respectively, *p<0.01). Immunohistochemistry of human aorta showed that expression of SCD1 was decreased in atherosclerotic lesions compared with non-atherosclerotic area. SCD1 mRNA expression in cultured HASMC was decreased by hydrogen peroxide (50μM). Furthermore, knockdown of SCD1 expression by using siRNA markedly increased palmitic acid - or stearic acid -induced BMP-2 expression and caspase-3 activation in HASMC. These effects were blunted by adenovirus-mediated SCD1-overexpression. In conclusion, these results demonstrate that saturated fatty acids promote osteogenic differentiation and eventual apoptosis of vascular smooth muscle cells, and suggest that SCD1 protects against these changes.