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PAI-1 contributes to homocysteine-induced cellular senescence. | LitMetric

PAI-1 contributes to homocysteine-induced cellular senescence.

Cell Signal

Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. Electronic address:

Published: December 2019

AI Article Synopsis

  • Cellular Senescence is linked to aging and related diseases, with PAI-1 being a key mediator and a possible target for therapy.
  • This study evaluates how PAI-1 inhibitors can counteract the effects of elevated homocysteine, which promotes cardiovascular aging by inducing cellular senescence.
  • Results show that PAI-1 inhibitors reduce indicators of senescence and improve cellular health in both lab and animal models, suggesting these inhibitors could be beneficial for cardiovascular health by mitigating homocysteine's harmful effects.

Article Abstract

Cellular Senescence is associated with organismal aging and related pathologies. Previously, we reported that plasminogen activator inhibitor-1 (PAI-1) is an essential mediator of senescence and a potential therapeutic target for preventing aging-related pathologies. In this study, we investigate the efficacies of PAI-1 inhibitors in both in vitro and in vivo models of homocysteine (Hcy)-induced cardiovascular aging. Elevated Hcy, a known risk factor of cardiovascular diseases, induces endothelial senescence as evidenced by increased senescence-associated β-Gal positivity (SA-β-Gal), flattened cellular morphology, and cylindrical appearance of cellular nuclei. Importantly, inhibition of PAI-1 by small molecule inhibitors reduces the number of SA-β-Gal positive cells, normalizes cellular morphology and nuclear shape. Furthermore, while Hcy induces the levels of senescence regulators PAI-1, p16, p53 and integrin β3, and suppresses catalase expression, treatment with PAI-1 inhibitors blocks the Hcy-induced stimulation of senescence cadres, and reverses the Hcy-induced suppression of catalase, indicating that PAI-1 specific small molecule inhibitors are efficient to prevent Hcy-induced cellular senescence. Our in vivo study shows that the levels of integrin β3, a recently identified potential regulator of cellular senescence, and its interaction with PAI-1 are significantly elevated in Hcy-treated heart tissues. In contrast, Hcy suppresses antioxidant gene regulator Nrf2 expression in hearts. However, co-treatment with PAI-1 inhibitor completely blocks the stimulation of Hcy-induced induction of integrin β3 and reverses Nrf2 expression. Collectively these in vitro and in vivo studies indicate that pharmacological inhibition of PAI-1 improves endothelial and cardiac health by suppressing the pro-senescence effects of hyperhomocysteinemia through suppression of Hcy-induced master regulators of cellular senescence PAI-1 and integrin β3. Therefore, PAI-1 inhibitors are promising drugs for amelioration of hyperhomocysteinemia-induced vascular aging and aging-related disease.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936332PMC
http://dx.doi.org/10.1016/j.cellsig.2019.109394DOI Listing

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