Investigation of low-dose ritonavir on human peripheral blood mononuclear cells using gene expression whole genome microarrays.
Ritonavir is a protease inhibitor associated with metabolic abnormalities and cardiovascular disease. We have investigated the effects of low-dose ritonavir treatment on gene expression in peripheral blood mononuclear cells (PBMC) of 10 healthy donors. Results using whole genome Illumina microarrays show that ritonavir modulates a number of genes implicated in lipid metabolism, inflammation and atherosclerosis. These candidate genes are dual specificity phosphatase 1 DUSP1), Kelch domain containing 3 (KLHDC3), neutral cholesterol ester hydrolase 1 (NCEH1) and acyl-CoA synthetase short-chain family member 2 (ACSS2). Validation experiments using quantitative PCR showed that ritonavir (at 100 mg once daily and 100 mg twice daily significantly down-regulated these 4 selected candidate genes in 20 healthy individuals. Lower expression levels of these 4 candidate genes, known to play a critical role in inflammation, lipid metabolism and atherosclerosis, may explain ritonavir adverse effects in patients.
Yilmaz
Saliha
S
Cardiovascular Division, King's College London, 150 Stamford Street, London, UK. saliha.yilmaz@kcl.ac.uk
Boffito
Marta
M
Collot-Teixeira
Sophie
S
De Lorenzo
Ferruccio
F
Waters
Laura
L
Fletcher
Carl
C
Back
David
D
Pozniak
Anton
A
Gazzard
Brian
B
McGregor
John Louis
JL
D000106:Acetate-CoA Ligase / Q000235:genetics; D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D002265:Carboxylic Ester Hydrolases / Q000235:genetics; D019295:Computational Biology; D015536:Down-Regulation / Q000187:drug effects; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019438:Ritonavir / Q000494:pharmacology*; D002787:Sterol Esterase
D015415:Biomarkers; D017320:HIV Protease Inhibitors; D002265:Carboxylic Ester Hydrolases; C515677:NCEH1 protein, human; D002787:Sterol Esterase; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D000106:Acetate-CoA Ligase; D019438:Ritonavir