NADPH oxidase 4 mediates upregulation of type 4 phosphodiesterases in human endothelial cells

Autor: Nilima Shukla, Gianni D Angelini, Jamie Y. Jeremy, Saima Muzaffar
Rok vydání: 2012
Předmět:
medicine.medical_specialty
Physiology
Angiogenesis
Vasodilator Agents
Clinical Biochemistry
Prostacyclin
Biology
Dinoprost
chemistry.chemical_compound
Downregulation and upregulation
Internal medicine
Human Umbilical Vein Endothelial Cells
medicine
Humans
Vasoconstrictor Agents
Gene Silencing
Iloprost
Enzyme Inhibitors
RNA
Small Interfering
NADPH oxidase
Tumor Necrosis Factor-alpha
Superoxide
Membrane Proteins
NADPH Oxidases
NOX4
Phosphodiesterase
Cell Biology
Cell cycle
Molecular biology
Cyclic Nucleotide Phosphodiesterases
Type 4
Up-Regulation
Isoenzymes
Alternative Splicing
Endocrinology
NADPH Oxidase 5
chemistry
NADPH Oxidase 4
15-Hydroxy-11 alpha
9 alpha-(epoxymethano)prosta-5
13-dienoic Acid
cardiovascular system
biology.protein
lipids (amino acids
peptides
and proteins)
Signal Transduction
medicine.drug
Zdroj: Journal of Cellular Physiology. 227:1941-1950
ISSN: 0021-9541
DOI: 10.1002/jcp.22922
Popis: The protective actions of prostacyclin (PGI(2) ) are mediated by cyclic AMP (cAMP) which is reduced by type 4 phosphodiesterases (PDE4) which hydrolyze cAMP. Superoxide (O2(-)) from NADPH oxidase (Nox) is associated with impaired PGI(2) bioactivity. The objective of this study, therefore, was to study the relationship between Nox and PDE4 expression in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated with the thromboxane A(2) analog, U46619, 8-isoprostane F(2α) (8IP), or tumor necrosing factor alpha (TNFα) [±iloprost (a PGI(2) analog)] and the expression of PDE4A, B, C, and D and splice variants thereof assessed using Western blotting and qPCR and mRNA silencing of Nox4 and Nox5. Effects on cell replication and angiogenesis were also studied. U46619, 8IP, and TNFα increased the expression of Nox 4 and Nox 5 and all PDE4 isoforms as well as cell replication and tubule formation (index of angiogenesis), effects inhibited by mRNA silencing of Nox4 (but not Nox5) and iloprost and rolipram. These data demonstrate that upregulation of Nox4 leads to an upregulation of PDE4A, B, and D and increased hydrolysis of cAMP which in turn augments cell replication and angiogenesis. This mechanism may be central to vasculopathies associated with endothelial dysfunction since the PGI(2)-cAMP signaling axis plays a key role in mediating functions that include hemostasis and angiogenesis.
Databáze: OpenAIRE
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