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PAI-1 contributes to homocysteine-induced cellular senescence.

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 ?-Gal positivity (SA-?-Gal), flattened cellular morphology, and cylindrical appearance of cellular nuclei. Importantly, inhibition of PAI-1 by small molecule inhibitors reduces the number of SA-?-Gal positive cells, normalizes cellular morphology and nuclear shape. Furthermore, while Hcy induces the levels of senescence regulators PAI-1, p16, p53 and integrin ?3, 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 ?3, 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 ?3 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 ?3. Therefore, PAI-1 inhibitors are promising drugs for amelioration of hyperhomocysteinemia-induced vascular aging and aging-related disease.

SUBMITTER: Sun T

PROVIDER: S-EPMC6936332 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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PAI-1 contributes to homocysteine-induced cellular senescence.

Sun Tianjiao T Ghosh Asish K AK Eren Mesut M Miyata Toshio T Vaughan Douglas E DE

Cellular signalling 20190828

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 endotheli ...[more]

PMID: 31472244

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Project description:BackgroundMechanical ventilation can cause acute atrophy and injury in the diaphragm, which are related to adverse clinical results. However, the underlying mechanisms of ventilation-induced diaphragm dysfunction (VIDD) have not been well elucidated. The current study aimed to explore the role of cellular senescence in VIDD.MethodsA total of twelve New Zealand rabbits were randomly divided into 2 groups: (1) spontaneously breathing anaesthetized animals (the CON group) and (2) mechanically ventilated animals (for 48 h) in V-ACV mode (the MV group). Respiratory parameters were collected during ventilation. Diaphragm were collected for further analyses.ResultsCompared to those in the CON group, the percentage and density of sarcomere disruption in the MV group were much higher (p < 0.001, both). The mRNA expression of MAFbx and MuRF1 was upregulated in the MV group (p = 0.003 and p = 0.006, respectively). Compared to that in the CON group, the expression of MAFbx and MuRF1 detected by western blotting was also upregulated (p = 0.02 and p = 0.03, respectively). Moreover, RNA-seq showed that genes associated with senescence were remarkably enriched in the MV group. The mRNA expression of related genes was further verified by q-PCR (Pai1: p = 0.009; MMP9: p = 0.008). Transverse cross-sections of diaphragm myofibrils in the MV group showed more intensive positive staining of SA-βGal than those in the CON group. p53-p21 axis signalling was elevated in the MV group. The mRNA expression of p53 and p21 was significantly upregulated (p = 0.02 and p = 0.05, respectively). The western blot results also showed upregulation of p53 and p21 protein expression (p = 0.03 and p = 0.05, respectively). Moreover, the p21-positive staining in immunofluorescence and immunohistochemistry in the MV group was much more intense than that in the CON group (p < 0.001, both).ConclusionsIn a rabbit model, we demonstrated that mechanical ventilation in A/C mode for 48 h can still significantly induce ultrastructural damage and atrophy of the diaphragm. Moreover, p53-dependent senescence might play a role in mechanical ventilation-induced dysfunction. These findings might provide novel therapeutic targets for VIDD.

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PAI-1 contributes to homocysteine-induced cellular senescence.

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PAI-1 contributes to homocysteine-induced cellular senescence.

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