Transcriptional and Post-Transcriptional Regulation of Thrombospondin-1 Expression: A Computational Model
Fig 8
Different therapeutic interventions to reduce TSP-1 levels in PAD.
(A) Hypoxia and TGFβ together contribute to a much higher intracellular TSP-1 protein expression in the simulated condition of CLI than the normoxic control condition (with no TGFβ). TSP-1 expression curves in response to different doses of (B) let-7 antagonists, (C) miR-18a mimics, and (D) p53 inhibitors. The effect of let-7 antagonist peaks at around 40 nM. (E) A combination of inhibiting both p53 production and NFAT activities achieve the most significant downregulation of TSP-1 in the simulated condition of CLI. In the simulations, the strength of NFAT inhibitor VIVIT is estimated from literature data to be a 70% decrease in the rate of calcineurin-mediated NFAT dephosphorylation when applied at micromolar doses [111]. (B-E) MiR-18a overexpression is simulated as an increase in the initial condition of precursor miR-18a; let-7 antagonists bind and sequester let-7 RISC with a Kd of 1 nM; small molecule inhibitor of p53 binds and sequesters cytoplasmic p53 with a Kd of 1 nM.