Details

Autor(en) / Beteiligte

• Sun, Tianjiao

Titel

Role of Plasminogen Activator Inhibitor-1 (PAI-1) in Endothelial Senescence and Cardiovascular Aging

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2020

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• Plasminogen activator inhibitor-1 (PAI-1) is an essential mediator of senescence and a potential therapeutic target for preventing aging-related pathologies. Cellular Senescence is associated with organismal aging and related pathologies. In our 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 Hcytreated heart tissues. In contrast, Hcy suppresses antioxidant gene regulator Nuclear factor erythroid 2-related factor 2 (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 prosenescence 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. Additionally, we have investigated the role of PAI-1 in other aging-related cardiovascular disease models, and especially we were interested in PAI-1's role in chronic kidney disease (CKD)-induced left ventricular hypertrophy (LVH). Although we did not see the effect of PAI-1 inhibition in ameliorating LVH in the adenine-induced CKD model, we provided the information to change to different models to study this role of PAI-1(more models were developed in other labs during the period of our study).