PAI-1 contributes to homocysteine-induced cellular senescence

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 th...

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Bibliographic Details
Published in:Cellular signalling 2019-12, Vol.64, p.109394-109394, Article 109394
Main Authors: Sun, Tianjiao, Ghosh, Asish K., Eren, Mesut, Miyata, Toshio, Vaughan, Douglas E.
Format: Article
Language:English
Subjects:
Catalase
Cellular senescence
Heart
Homocysteine
Integrin β3
Nrf2
PAI-1
TM5441
TM5A15
Vascular endothelial cells
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Summary: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. [Display omitted] •High level of homocysteine induces cellular senescence in vitro and in vivo.•PAI-1 inhibitors TM5441 and TM5A15 efficiently block homocysteine-induced cellular and cardiac senescence through suppression of senescence regulators PAI-1, p16, p21, p53 and integrin β3.•Homocysteine induces the levels of integrin β3, a senescence regulator, in human coronary artery endothelial cel
ISSN:0898-6568
1873-3913
DOI:10.1016/j.cellsig.2019.109394