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- Title
T0901317, an LXR agonist, augments PKA-induced vascular cell calcification
- Authors
Hsu, Jeffrey J.; Lu, Jinxiu; Huang, Michael S.; Geng, Yifan; Sage, Andrew P.; Bradley, Michelle N.; Tontonoz, Peter; Demer, Linda L.; Tintut, Yin
- Abstract
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 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.
- Subjects
LIGANDS (Biochemistry); NUCLEAR receptors (Biochemistry); ATHEROSCLEROSIS treatment; PROTEIN kinases; CALCIFICATION; ALKALINE phosphatase; THERAPEUTICS
- Publication
FEBS Letters, 2009, Vol 583, Issue 8, p1344
- ISSN
0014-5793
- Publication type
Article
- DOI
10.1016/j.febslet.2009.03.039