title: T0901317, an LXR agonist, augments PKA-induced vascular cell calcification.
abstract: 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 Lxrbeta(-/-)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.
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, CHS A2-237, 10833 Le Conte Avenue, Los Angeles, CA 90095-1679, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hsu
authors.forename: Jinxiu
authors.initials: J
authors.lastname: Lu
authors.forename: Michael S
authors.initials: MS
authors.lastname: Huang
authors.forename: Yifan
authors.initials: Y
authors.lastname: Geng
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Sage
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Bradley
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
authors.forename: Linda L
authors.initials: LL
authors.lastname: Demer
authors.forename: Yin
authors.initials: Y
authors.lastname: Tintut