Angiogenic transcriptome of human microvascular endothelial cells: Effect of hypoxia, modulation by atorvastatin.
Hypoxia changes expression of angiogenic genes. Statins were also reported to affect blood vessel formation. However, data on the effects of statins on endothelial cells in hypoxia are limited. Here, effect of hypoxia and atorvastatin was assessed in human microvascular endothelial cells (HMEC-1). Hypoxia (1% O2) up-regulated vascular endothelial growth factor-A (VEGF-A) but, unexpectedly, it decreased interleukin-8 (IL-8) and placenta growth factor (PlGF) expression. Atorvastatin (0.1-1 microM) attenuated PlGF in HMEC-1 in normoxia while it decreased VEGF-A and IL-8 production both in normoxia and hypoxia. Notably, the expression of VEGF-D, macrophage scavenger receptor-1 (MSR1), transforming growth factor beta receptor III (TGFbetaR3) and inhibitor of DNA binding 3 (ID3) was augmented by atorvastatin in cells cultured in normoxia, while in hypoxia the statin attenuated their expression. These data showed that hypoxia influenced in the opposite way the expression of major endothelial genes, augmenting VEGF-A and decreasing IL-8 and PlGF. The influence of atorvastatin on angiogenic gene expression is complex, and final pro- or anti-angiogenic outcome of statin therapy remains to be established for numerous angiogenesis-related diseases.
Department of Medical Biotechnology, Faculty of Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
Agnieszka
A
Loboda
Agnieszka
A
Jazwa
Alicja
A
Jozkowicz
Grietje
G
Molema
Jozef
J
Dulak
D000069059:Atorvastatin; D015687:Cell Hypoxia; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016209:Interleukin-8; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D011758:Pyrroles; D012333:RNA, Messenger; D019700:Thrombospondin 1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D000069059:Atorvastatin