HO-1 Induced by Cilostazol Protects Against TNF-α-associated Cytotoxicity via a PPAR-γ-dependent Pathway in Human Endothelial Cells

Abstract

A large body of evidence has indicated that induction of endogenous antioxidative proteins seems to be a reasonable strategy for delaying the progression of cell injury. In our previous study, cilostazol was found to increase the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) in synovial cells. Thus, the present study was undertaken to examine whether cilostazol is able to counteract tumor necrosis factor-α (TNF-α )-induced cell death in endothelial cells via the induction of HO-1 expression. W e exposed human umbilical vein endothelial cells (HUVECs) to TNF-α (50 ng/ml), with or without cilostazol (10 μ M). Pretreatment with cilostazol markedly reduced TNF-α -induced viability loss in the HUVECs, which was reversed by zinc protoporphyrine IX (ZnPP), an inhibitor of HO-1. Moreover, cilostazol increased HO-1 protein and mRNA expression. Cilostazol-induced HO-1 induction was markedly attenuated not only by ZnPP but also by copper-protoporphyrin IX (CuPP). In an assay measuring peroxisome proliferator-activated receptor-γ (PPAR-γ ) transcription activity, cilostazol directly increased PPAR-γ transcriptional activity which was completely abolished by HO-1 inhibitor. Furthermore, increased PPAR-γ activity by cilostazol and rosiglitazone was completely abolished in cells transfected with HO-1 siRNA. Taken together, these results indicate that cilostazol up-regulates HO-1 and protects cells against TNF-α -induced endothelial cytotoxicity via a PPAR-γ -dependent pathway.

Signal transduction involved in lipoxin A4-induced protection of tubular epithelial cells against hypoxia/reoxygenation injury

“…5A). Similarly, previous studies indicated that HO-1 induction was upregulated by PPARγ in human smooth muscle cells and vascular endothelial cells (34), and cilostazol, an inhibitor of phosphodiesterase type III, protected endothelial cells against tumor necrosis factor-α-induced cytotoxicity through HO-1 induction via a PPARγ-dependent pathway (43). …”

Fucoidan from Fucus vesiculosus Protects against Alcohol-Induced Liver Damage by Modulating Inflammatory Mediators in Mice and HepG2 Cells

“…Hemeoxygenase-1 (HO-1) is an inducible form of the rate-limiting enzyme involved in heme catabolism. In preclinical models of tissue injury, HO-1 has been shown to confer cellular protection through inhibition of apoptosis, inflammation and cell proliferation [ 14 , 15 ]. To combat alcohol-induced liver damage, strategies to strengthen the protective effects of molecules, such as HO-1, and the development of new ways to reduce liver-damaging signals may be favorable treatment options.…”

The PPARγ agonist, rosiglitazone, attenuates airway inflammation and remodeling via heme oxygenase-1 in murine model of asthma

“…According to previous literatures, heme oxygenase (HO)-1 was suggested as one of the down-stream effectors of PPARγ [11,13] . Our previous work showed that HO-1 could upregulate expression of p21 protein [10] which was considered as an inhibitor of cell proliferation.…”