SIRT1 upregulators from high-throughput screening as anti-proliferation and anti-migration agents in vascular smooth muscle cells (654.2)

Abstract

Objective: To establish a cell-based drug screening system for discovering up-regulators of SIRT1 and confirmed their biological activities in rat aortic VSMCs. Methods and Results: A stable transfected with a human SIRT1-promoter-luciferase reporter gene construct cell line was obtained in 293A cells. Using Resveratrol as a positive control, a cell-based SIRT1 up-regulator high-throughput screening (HTS) model was established in a 384-well microplate format. Of 27,274 compounds, 86 compounds were identified to up-regulate SIRT1 transcriptional activity in the cell-based reporter assay. Furthermore, 10 compounds including a series of Resveratrol analogues showing low toxic in both VSMCs and HUVECs were demonstrated to not only stimulate the expression of SIRT1 on the transcriptional level in VSMCs, but also have anti-proliferation and anti-migration properties in PDGF-BB (40 ng/ml)-stimulated VSMCs. In addition, several natural compounds (Baicalin, Genistein, Chrysin, etc.) were identified to elevate SIRT1 transcriptional level, with the reported property of attenuating neointima formation following injury via suppression of VSMC proliferation, migration or both. Conclusion: A cell-based drug screening model was established to screen SIRT1 up-regulators. The active compounds originated from this HTS assay may be developed to drug candidates or lead compounds for new anti-restenosis drugs.

Grant Funding Source: This work was supported by the National Natural Science Foundation of China (No. 81102444).