New thiazolidinediones affect endothelial cell activation and angiogenesis

Author(s)

Rudnicki, Martina ^[1] ; Tripodi, Gustavo L. ^[1] ; Ferrer, Renila ^[1] ; Bosca, Lisardo ^[2] ; Pitta, Marina G. R. ^[3] ; Pitta, Ivan R. ^[3] ; Abdalla, Dulcineia S. P. ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo, SP - Brazil

^[2] CSIC UAM, Inst Invest Biomed Alberto Sols, Madrid - Spain

^[3] Univ Fed Pernambuco, Core Therapeut Innovat, Recife, PE - Brazil

• Document type: Journal article
• Source: European Journal of Pharmacology; v. 782, p. 98-106, JUL 5 2016.
• Web of Science Citations: 5

Abstract

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists used in treating type 2 diabetes that may exhibit beneficial pleiotropic effects on endothelial cells. In this study, we characterized the effects of three new TZDs {[}GQ-32 (3-biphenyl-4-ylmethyl 5 (4 nitro benzylidene)thiazolidine-2,4-dione), GQ-169 (5-(4-chloro-benzylidene)-3-(2,6-dichloro-benzyl)-thiazolidine-2,4-dione ), and LYSO-7 (5-(5-bromo-1H-indol-3-ylmethylene)-3-(4-chlorobenzyl)-thiazolidine-2,4- dione)] on endothelial cells. The effects of the new TZDs were evaluated on the production of nitric oxide (NO) and reactive oxygen species (ROS), cell migration, tube formation and the gene expression of adhesion molecules and angiogenic mediators in human umbilical vein endothelial cells (HUVECs). PPAR gamma activation by new TZDs was addressed with a reporter gene assay. The three new TZDs activated PPAR gamma and suppressed the tumor necrosis factor alpha-induced expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. GQ-169 and LYSO-7 also inhibited the glucose-induced ROS production. Although NO production assessed with 4-amino-5-methylamino-2',7'-difluorofluorescein-FM probe indicated that all tested TZDs enhanced intracellular levels of NO, only LYSO-7 treatment significantly increased the release of NO from HUVEC measured by chemiluminescence analysis of culture media. Additionally, GQ-32 and GQ-169 induced endothelial cell migration and tube formation by the up-regulation of angiogenic molecules expression, such as vascular endothelial growth factor A and interleukin 8. GQ-169 also increased the mRNA levels of basic fibroblast growth factor, and GQ-32 enhanced transforming growth factor-beta expression. Together, the results of this study reveal that these new TZDs act as partial agonists of PPAR gamma and modulate endothelial cell activation and endothelial dysfunction besides to stimulate migration and tube formation. (C) 2016 Elsevier B.V. All rights reserved. (AU)

• FAPESP's process: 12/51316-5 - Study of the activity of biodrugs, PPARs agonists and natural products with therapeutic potential in atherosclerosis
• Grantee: Dulcineia Saes Parra Abdalla
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 11/24020-5 - Evaluation of angiogenic properties and cardiac effects of new arylidene-thiazolidinediones
• Grantee: Renila Ferrer
• Support Opportunities: Scholarships in Brazil - Scientific Initiation