T0901317, an LXR agonist, augments PKA-induced vascular cell calcification

• Published in: FEBS letters 2009-04, Vol.583 (8), p.1344-1348
• Main Authors: Hsu, Jeffrey J., Lu, Jinxiu, Huang, Michael S., Geng, Yifan, Sage, Andrew P., Bradley, Michelle N., Tontonoz, Peter, Demer, Linda L., Tintut, Yin
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Calcification; Calcinosis; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases - metabolism; DNA Primers; DNA-Binding Proteins - agonists; DNA-Binding Proteins - genetics; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Endothelium, Vascular - pathology; Hydrocarbons, Fluorinated - pharmacology; Liver X receptor; Liver X Receptors; Mice; Mice, Knockout; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - genetics; Smooth muscle cell; Sulfonamides - pharmacology; T0901317
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2009.03.039

We examined the effect of liver X receptor (LXR) agonists on vascular calcification, prevalent in atherosclerotic lesions. T0901317, an LXR agonist, augmented protein kinase A (PKA)-induced mineralization and alkaline phosphatase (ALP) activity in aortic smooth muscle cells isolated from wild-type, but not from Lxrβ −/−mice. A six-hour T0901317 treatment augmented the PKA-induced expression of the phosphate transporter Pit-1, a positive regulator of mineralization, suggesting a direct role. A ten-day T0901317 treatment attenuated PKA-induced expression of mineralization inhibitors, osteopontin and ectonucleotide pyrophosphatase/phosphodiesterase-1, suggesting an indirect role. The effects of T0901317 were attenuated by inhibition of ALP, Pit-1 and Rho-associated kinase, but not by inhibition of PKA. These results suggest that T0901317-augmented mineralization occurs downstream of PKA, involving both direct and indirect LXR-mediated pathways.