Curcumin induces oxidation-dependent cell cycle arrest mediated by SIRT7 inhibition of rDNA transcription in human aortic smooth muscle cells

Abstract

It is widely accepted that abnormal accumulation of vascular smooth muscle cells (VSMCs) may promote atherosclerosis and post-angioplasty restenosis. The use of some plant polyphenols with potent antiproliferative activities may be considered as a therapeutic intervention to diminish/prevent the development of cardiovascular pathologies. In the present study, VSMC response to curcumin treatment was evaluated. 5μM curcumin elicited a cytostatic effect, which was accompanied by protein carbonylation, oxidative DNA damage and changes in the nucleolar activity (the size and number of nucleoli, nucleolar protein levels and their localization). The levels of p53 and p21 were elevated. However, this was independent of DNA DSBs. Curcumin caused inhibition of rDNA transcription, which could be due to SIRT7 downregulation, site-specific methylation of RNA18S5 gene promoter or both. Curcumin-induced DNA methyltransferase 2 (DNMT2) upregulation was also shown. DNMT2-mediated RNA methylation could promote RNA stabilization upon curcumin treatment. In conclusion, a nucleolus-focused cytostatic action of curcumin at a low micromolar concentration range, which could be feasibly achieved through dietary means, was established in VSMCs and we propose a novel mechanism underlying this action. We believe that our results may contribute to better understanding of the biological and pharmacological effects of curcumin on the human cardiovascular system.