Oxidative stress modulates PPARγ in vascular endothelial cells

Abstract

The peroxisome proliferator-activated receptor gamma (PPARγ) plays an important role in vascular regulation. However, the impact of oxidative stress on PPARγ expression and activity has not been clearly defined. Human umbilical vein endothelial cells (HUVECs) were exposed to graded concentrations of H 2 O 2 for 0.5-72 h, or bovine aortic endothelial cells (BAECs) were exposed to alterations in extracellular thiol/disulfide redox potential (E h ) of the cysteine (Cys)/cystine (CySS) couple. Within 2 h, H 2 O 2 reduced HUVEC PPARγ mRNA and activity and reduced the expression of two PPARγ-regulated genes without altering PPARγ protein levels. After 4 h H 2 O 2 exposure, mRNA levels remained reduced while PPARγ activity returned to control levels. PPARγ mRNA levels remained depressed for up to 72 h after exposure to H 2 O 2 , without any change in PPARγ activity. Catalase prevented H 2 O 2 -induced reductions in PPARγ mRNA and activity. H 2 O 2 1) reduced luciferase expression in HUVECs transiently transfected with a human PPARγ promoter reporter, 2) failed to alter PPARγ mRNA half-life, and 3) transiently increased expression and activity of c-Fos and phospho-c-Jun. Treatment with the AP-1 inhibitor, curcumin, prevented H 2 O 2 -mediated reductions in PPARγ expression. In addition, media having an oxidized E h reduced BAEC PPARγ mRNA and activity. These findings demonstrate that oxidative stress, potentially through activation of inhibitory redox-regulated transcription factors, attenuates PPARγ expression and activity in vascular endothelial cells through suppression of PPARγ transcription.

The Nox4 Inhibitor GKT137831 Attenuates Hypoxia-Induced Pulmonary Vascular Cell Proliferation

“…For example, the current study and others have demonstrated that hypoxia significantly reduces PPARg expression in the lung (17) and in vascular wall cells (12). Coupled with evidence that hypoxia selectively upregulates Nox4 in the lung (10), that Nox4 generates H 2 O 2 (26,27), and that H 2 O 2 reduces PPARg expression in endothelial cells (42), these findings indicate that Nox4-derived ROS mediate reductions in PPARg during hypoxia. Consistent with this postulate, GKT137831 attenuates hypoxia-induced reductions in PPARg expression and HPAEC and HPASMC proliferation in vitro in the current study.…”

“…Loss of PPARg is associated with SMC proliferation, migration, and vascular remodeling (43). The mechanisms by which Nox4 reduces PPARg may relate to H 2 O 2 -mediated activation of the transcription factor AP1, which negatively regulates PPARg (42). Furthermore, pulmonary vascular tissue from patients with IPAH demonstrates reduced PPARg (15) and increased Nox4 expression (10).…”

Thin endometrium transcriptome analysis reveals a potential mechanism of implantation failure

“…These genes have essential roles in the response to oxidative stress 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25…”

“…These genes included PPAR‐ γ, XDH , CBR3 , IDH1 , and CPT1 , which have essential roles in the cellular responses to oxidative stress. The activation of PPAR‐ γ is an important factor in the protection against oxidative stress in cells, such as vascular endothelial cells and cardiomyocytes 16, 17, 20, 21, 24, 25. Xanthine dehydrogenase reduces age‐related oxidative stress in tissues and immune cells 23.…”

Thiazolidinedione or Rhodanine: A Study on Synthesis and Anticancer Activity Comparison of Novel Thiazole Derivatives

“…More interestingly, numerous compounds containing the TZD ring have been developed as potential anticancer agents (3)(4). TZDs, which are anti-cancer therapeutics for the most common types of cancers including, lung, breast, and colon, have been explored for the PPAR-γ-dependent and -independent mechanisms by which TZDs exert their antitumor effects (5). Rhodanines have been reported to possess antibacterial, antifungal, antiviral, antimalarial, insecticidal, herbicidal, antitumor, anti-inflammatory and cardiotonic activities (6)(7).…”