The effects of phosphodiesterase inhibitor,pentoxifylline, on human endothelial function
Date Issued
2009
Date
2009
Author(s)
Tsai, Ching-Wei
Abstract
Endothelial dysfunction is thought to play a key role in the evolution and progression of CKD and may be one major culprit for the development of cardiovascular disease. Biomarkers of endothelial dysfunction are higher in patients with CKD and correlate inversely with glomerular filtration rate. Thus, understanding of the mechanisms responsible for endothelial dysfunction in association with CKD is important for the development of novel renoprotective therapeutic strategies.yclic nucleotide phosphodiesterases (PDEs) play a critical role in regulating cellular functions through modulation of cyclic nucleotides, cAMP and cGMP. Endothelial cells are known to contain PDE2, PDE3, PDE4, and PDE5. Previously, a nonselective PDE inhibitor, pentoxifylline, has shown its anti-inflammatory, anti-proliferative, and anti-fibrotic effects in renal mesangial cells, tubular cells, and fibroblasts. Whether or not pentoxifylline can modulate endothelial dysfunction in endothelial cells has never been investigated.n this study, the optimal working concentration of pentoxifylline on human umbilical vein endothelial cells (HUVECs) was first determined by MTT and lactate dehydrogenase assays; next, tumor necrosis factor-alpha (TNF-α)-elicited expression of adhesion molecules and inflammatory cytokines in HUVECs were measured and used as biomarkers of endothelial dysfunction. Finally, the effectiveness of pentoxifylline on biomarkers of endothelial dysfunction was investigated. Our results showed that TNF-α could induce the secretion of soluble ICAM-1 and VCAM-1, and augment the expression of CCL2/MCP-1 and CX3CL1/fractalkine mRNAs. These inflammatory biomarkers of HUVECs could be siginificantly suppressed by pentoxifylline. As such, pentoxifylline can antagonize TNF-α-induced endothelial dysfunction through inhibition of the expression of adhesion molecules and chemotactic cytokines. These results imply a potential therapeutic role of pentoxifylline in the treatment of vascular disorders characterized by endothelial dysfunction, such as atherosclerosis.
Subjects
Endothelial dysfunction
phosphodiesterases inhibitor
adhesion molecules
chemokine
SDGs
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