Pentoxifylline potentiates nitric oxide production in interleukin-1beta-stimulated vascular smooth muscle cells through cyclic AMP-dependent protein kinase A pathway.
In the present study, we observed that pentoxifylline (PTX) significantly augmented the nitric oxide (NO) production and the iNOS gene expression by interleukin-1beta (IL-1beta)-stimulated vascular smooth muscle cells (VSMCs). The enhancing effects of PTX on the IL-1beta-induced NO production was associated with an increased intracellular cyclic AMP (cAMP) levels, and the synergistic effects of PTX on the IL-1beta-induced NO production was blocked by cAMP-dependent protein kinase A (PKA) inhibitors. PKA inhibitors, KT5720 and H89, markedly decreased the augmented expression of iNOS gene whereas ODQ, a soluble guanylate cyclase inhibitor, did not affect the enhancing effect. In addition, the pretreatment with KT5720 or H89 abolished the increased translocation of the p65 subunit of NF-kappaB into the nucleus by PTX in the IL-1beta-stimulated VSMCs. These results suggest that enhancing effects of PTX on the iNOS gene expression in the IL-1beta-stimulated VSMCs is mediated predominantly through the activation of NF-kappaB via cAMP-dependent PKA pathway.
Kim
N Y
NY
Department of Microbiology and Immunology, School of Medicine, Wonkwang University, Iksan, 570-749, Chonbuk, South Korea.
Pae
H O
HO
Kim
Y C
YC
Choi
C K
CK
Rim
J S
JS
Lee
H S
HS
Kim
Y M
YM
Chung
H T
HT
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000032:analysis / Q000502:physiology*; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism; D004357:Drug Synergism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010431:Pentoxifylline / Q000494:pharmacology*; D051381:Rats; D051996:Transcription Factor RelA; D014665:Vasodilator Agents / Q000494:pharmacology*
D007375:Interleukin-1; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D010431:Pentoxifylline