Systems pharmacology identifies an arterial wall regulatory gene network mediating coronary artery disease side effects of antiretroviral therapy

Itziar Frades, Benjamin Readhead, Letizia Amadori, Simon Koplev, Husain A. Talukdar, Heidi M. Crane, Paul K. Crane, Jason C. Kovacic, Joel T. Dudley, Chiara Giannarelli, Johan L.M. Björkegren, Inga Peter

Research output: Contribution to journalArticle

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 genegene 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 esterloaded 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.

Original languageEnglish (US)
Pages (from-to)262-272
Number of pages11
JournalCirculation: Genomic and Precision Medicine
Volume12
Issue number6
DOIs
StatePublished - Jan 1 2019

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Gene Regulatory Networks
Coronary Artery Disease
Pharmacology
Foam Cells
Nelfinavir
Saquinavir
Drug Therapy
Ritonavir
Atherosclerosis
Therapeutics
Esters
Dyslipidemias
RNA Interference
Genetic Therapy
Genes
Libraries
HIV Infections
RNA
Phenotype
Gene Expression

Keywords

  • Antiretroviral therapy
  • Atherosclerosis
  • Highly active
  • HIV
  • Nelfinavir
  • Ritonavir
  • Saquinavir

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Cite this

Systems pharmacology identifies an arterial wall regulatory gene network mediating coronary artery disease side effects of antiretroviral therapy. / Frades, Itziar; Readhead, Benjamin; Amadori, Letizia; Koplev, Simon; Talukdar, Husain A.; Crane, Heidi M.; Crane, Paul K.; Kovacic, Jason C.; Dudley, Joel T.; Giannarelli, Chiara; Björkegren, Johan L.M.; Peter, Inga.

In: Circulation: Genomic and Precision Medicine, Vol. 12, No. 6, 01.01.2019, p. 262-272.

Research output: Contribution to journalArticle

Frades, I, Readhead, B, Amadori, L, Koplev, S, Talukdar, HA, Crane, HM, Crane, PK, Kovacic, JC, Dudley, JT, Giannarelli, C, Björkegren, JLM & Peter, I 2019, 'Systems pharmacology identifies an arterial wall regulatory gene network mediating coronary artery disease side effects of antiretroviral therapy', Circulation: Genomic and Precision Medicine, vol. 12, no. 6, pp. 262-272. https://doi.org/10.1161/CIRCGEN.118.002390
Frades, Itziar ; Readhead, Benjamin ; Amadori, Letizia ; Koplev, Simon ; Talukdar, Husain A. ; Crane, Heidi M. ; Crane, Paul K. ; Kovacic, Jason C. ; Dudley, Joel T. ; Giannarelli, Chiara ; Björkegren, Johan L.M. ; Peter, Inga. / Systems pharmacology identifies an arterial wall regulatory gene network mediating coronary artery disease side effects of antiretroviral therapy. In: Circulation: Genomic and Precision Medicine. 2019 ; Vol. 12, No. 6. pp. 262-272.
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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 genegene 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 esterloaded 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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AU - Readhead, Benjamin

AU - Amadori, Letizia

AU - Koplev, Simon

AU - Talukdar, Husain A.

AU - Crane, Heidi M.

AU - Crane, Paul K.

AU - Kovacic, Jason C.

AU - Dudley, Joel T.

AU - Giannarelli, Chiara

AU - Björkegren, Johan L.M.

AU - Peter, Inga

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N2 - 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 genegene 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 esterloaded 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.

AB - 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 genegene 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 esterloaded 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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