Itziar Frades1, Ben Readhead1,2,3,4, Letizia Amadori1, Simon Koplev1, Husain A Talukdar5, Heidi M Crane6, Paul K Crane6, Jason C Kovacic7,8, Joel T Dudley1,2,3, Chiara Giannarelli1,8,9, Johan L M Björkegren1,2,5, Inga Peter1,2. 1. Department of Genetics and Genomic Sciences (I.F., B.R., L.A., S.K., J.T.D., C.G., J.L.M.B., I.P.), Icahn School of Medicine at Mount Sinai, New York, NY. 2. Icahn Institute for Data Science and Genomic Technology (B.R., J.T.D., J.L.M.B., I.P.), Icahn School of Medicine at Mount Sinai, New York, NY. 3. Institute for Next Generation Healthcare (B.R., J.T.D.), Icahn School of Medicine at Mount Sinai, New York, NY. 4. ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe (B.R.). 5. Department of Medicine, Integrated Cardio Metabolic Centre, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden (H.A.T., J.L.M.B.). 6. Department of Medicine, University of Washington, Seattle (H.M.C., P.K.C.). 7. Department of Medicine (J.C.K.), Icahn School of Medicine at Mount Sinai, New York, NY. 8. Cardiovascular Research Center (J.C.K., C.G.), Icahn School of Medicine at Mount Sinai, New York, NY. 9. Precision Immunology Institute (C.G.), Icahn School of Medicine at Mount Sinai, New York, NY.
Abstract
BACKGROUND: Antiretroviral therapy (ART) for HIV infection increases risk for coronary artery disease (CAD), presumably by causing dyslipidemia and increased atherosclerosis. We applied systems pharmacology to identify and validate specific regulatory gene networks through which ART drugs may promote CAD. METHODS: Transcriptional responses of human cell lines to 15 ART drugs retrieved from the Library of Integrated Cellular Signatures (overall 1127 experiments) were used to establish consensus ART gene/transcriptional signatures. Next, enrichments of differentially expressed genes and gene-gene connectivity within these ART-consensus signatures were sought in 30 regulatory gene networks associated with CAD and CAD-related phenotypes in the Stockholm Atherosclerosis Gene Expression study. RESULTS: Ten of 15 ART signatures were significantly enriched both for differential expression and connectivity in a specific atherosclerotic arterial wall regulatory gene network (AR-RGN) causal for CAD involving RNA processing genes. An atherosclerosis in vitro model of cholestryl ester-loaded foam cells was then used for experimental validation. Treatments of these foam cells with ritonavir, nelfinavir, and saquinavir at least doubled cholestryl ester accumulation ( P=0.02, 0.0009, and 0.02, respectively), whereas RNA silencing of the AR-RGN top key driver, PQBP1 (polyglutamine binding protein 1), significantly curbed cholestryl ester accumulation following treatment with any of these ART drugs by >37% ( P<0.05). CONCLUSIONS: By applying a novel systems pharmacology data analysis framework, 3 commonly used ARTs (ritonavir, nelfinavir, and saquinavir) were found altering the activity of AR-RGN, a regulatory gene network promoting foam cell formation and risk of CAD. Targeting AR-RGN or its top key driver PQBP1 may help reduce CAD side effects of these ART drugs.
BACKGROUND: Antiretroviral therapy (ART) for HIV infection increases risk for coronary artery disease (CAD), presumably by causing dyslipidemia and increased atherosclerosis. We applied systems pharmacology to identify and validate specific regulatory gene networks through which ART drugs may promote CAD. METHODS: Transcriptional responses of human cell lines to 15 ART drugs retrieved from the Library of Integrated Cellular Signatures (overall 1127 experiments) were used to establish consensus ART gene/transcriptional signatures. Next, enrichments of differentially expressed genes and gene-gene connectivity within these ART-consensus signatures were sought in 30 regulatory gene networks associated with CAD and CAD-related phenotypes in the Stockholm Atherosclerosis Gene Expression study. RESULTS: Ten of 15 ART signatures were significantly enriched both for differential expression and connectivity in a specific atherosclerotic arterial wall regulatory gene network (AR-RGN) causal for CAD involving RNA processing genes. An atherosclerosis in vitro model of cholestryl ester-loaded foam cells was then used for experimental validation. Treatments of these foam cells with ritonavir, nelfinavir, and saquinavir at least doubled cholestryl ester accumulation ( P=0.02, 0.0009, and 0.02, respectively), whereas RNA silencing of the AR-RGN top key driver, PQBP1 (polyglutamine binding protein 1), significantly curbed cholestryl ester accumulation following treatment with any of these ART drugs by >37% ( P<0.05). CONCLUSIONS: By applying a novel systems pharmacology data analysis framework, 3 commonly used ARTs (ritonavir, nelfinavir, and saquinavir) were found altering the activity of AR-RGN, a regulatory gene network promoting foam cell formation and risk of CAD. Targeting AR-RGN or its top key driver PQBP1 may help reduce CAD side effects of these ART drugs.
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