Yijian Chen1, Yongliang Zheng2, Liping Liu1, Chuanming Lin1, Changfeng Liao1, Liuyan Xin1, Sisi Zhong1, Qilai Cheng3, Liqun Zhang4. 1. Hematology Department, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China. 2. Hematology Department, The Affiliated Hospital of Jinggangshan University, Ji'an, China. 3. College of Pharmacy, Gannan Medical University, Ganzhou, China. 4. Quality Control Department, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
Abstract
BACKGROUND: Tumor necrosis factor (TNF)-α can upregulate the expression of plasminogen activator inhibitor (PAI)-1, an inhibitor of fibrinolysis. Adiponectin (Adp) antagonizes TNF-α by negatively regulating its expression in various tissues. In the present study, the ability of Adp to suppress TNF-α-induced PAI-1 upregulation and the underlying mechanisms were evaluated. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with TNF-α in the presence or absence of Adp, and PAI-1 mRNA and antigen expression, activated signaling pathways, and molecular mechanisms were analyzed by qRT-PCR and ELISA. RESULTS: Adp decreased the TNF-α-induced upregulation of PAI-1 mRNA and protein expression and suppressed TNF-α-induced cAMP-PKA-AMPK inactivation. Adp also suppressed the TNF-α-induced NF-kB binding capability on the PAI-1 promoter. Moreover, these Adp-induced effects were further enhanced or prevented by treatment with the cAMP inhibitor Rp-cAMPs or activator forskolin, respectively. CONCLUSIONS: Our data suggest that Adp abrogates TNF-α-activated PAI-1 expression by activating cAMP-PKA-AMPK signaling to suppress NF-kB binding to the PAI-1 promoter in HUVECs. Given the antifibrotic effect of PAI-1 abrogation, Adp may be utilized as a novel agent in the treatment of fibrotic diseases.
BACKGROUND: Tumor necrosis factor (TNF)-α can upregulate the expression of plasminogen activator inhibitor (PAI)-1, an inhibitor of fibrinolysis. Adiponectin (Adp) antagonizes TNF-α by negatively regulating its expression in various tissues. In the present study, the ability of Adp to suppress TNF-α-induced PAI-1 upregulation and the underlying mechanisms were evaluated. METHODS:Human umbilical vein endothelial cells (HUVECs) were treated with TNF-α in the presence or absence of Adp, and PAI-1 mRNA and antigen expression, activated signaling pathways, and molecular mechanisms were analyzed by qRT-PCR and ELISA. RESULTS:Adp decreased the TNF-α-induced upregulation of PAI-1 mRNA and protein expression and suppressed TNF-α-induced cAMP-PKA-AMPK inactivation. Adp also suppressed the TNF-α-induced NF-kB binding capability on the PAI-1 promoter. Moreover, these Adp-induced effects were further enhanced or prevented by treatment with the cAMP inhibitor Rp-cAMPs or activator forskolin, respectively. CONCLUSIONS: Our data suggest that Adp abrogates TNF-α-activated PAI-1 expression by activating cAMP-PKA-AMPK signaling to suppress NF-kB binding to the PAI-1 promoter in HUVECs. Given the antifibrotic effect of PAI-1 abrogation, Adp may be utilized as a novel agent in the treatment of fibrotic diseases.
Authors: Luis D'Marco; Valery Morillo; José Luis Gorriz; María K Suarez; Manuel Nava; Ángel Ortega; Heliana Parra; Nelson Villasmil; Joselyn Rojas-Quintero; Valmore Bermúdez Journal: J Diabetes Res Date: 2021-11-08 Impact factor: 4.011