Premium
HIV protease inhibitors activate the unfolded protein response and promote foam cell formation in macrophages
Author(s) -
Zhou Huiping,
Jarujaron Sirikalaya,
Ding Hong,
Pandak William M.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1126-d
Subject(s) - unfolded protein response , foam cell , western blot , intracellular , protease , chop , cytokine , apoptosis , cell , immunology , microbiology and biotechnology , chemistry , macrophage , biology , medicine , endoplasmic reticulum , in vitro , enzyme , biochemistry , gene
Numerous clinic studies have suggested that HIV protease inhibitors (PIs) are closely linked to atherosclerotic cardiovascular disease. However, the exact mechanisms underling the HIV PI‐induced atherosclerosis are still unclear. Macrophages play essential roles in both early atherosclerotic lesion development and late lesion complications. Our previous studies demonstrated that HIV PI (ritonavir) activated the unfolded protein response (UPR), significantly increased apoptosis, and promoted foam cell formation in macrophages. The current study further examines whether all of the HIV PIs have the similar effects on the UPR activation, inflammatory cytokine release, and foam cell formation. Methods Mouse J774A.1 cells were used in this study. Expression of the UPR responsive genes, including CHOP, ATF‐4 and XBP‐1 were detected by Western Blot analysis. TNF‐α and IL‐6 levels in the media were determined by enzyme‐linked immunosorbent assay. Intracellular lipids were detected with Oil Red O staining. Results All HIV PIs, except amprenavir, activated the UPR, induced TNF‐α and IL‐6 release, and promoted foam cell formation to varying degrees. Conclusions These results suggest that HIV PIs differ greatly in their ability to activate the UPR, increase inflammatory cytokine release and promote foam cell formation in macrophages. These results provide critical information for a better understanding of the cellular mechanisms of HIV PI‐associated atherosclerosis and developing new therapeutic strategies to avoid some of the adverse side effects caused by current HIV PIs. This work is supported by grants from the National Institutes of Health (R01 AI057189, P01 DK38030), GlaxoSmithKline research fund and A.D. Williams fund.