ArticleCirculation. Genomic and precision medicine2019
Systems Pharmacology Identifies an Arterial Wall Regulatory Gene Network Mediating Coronary Artery Disease Side Effects of Antiretroviral Therapy.
Article in Circulation. Genomic and precision medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 12 citations in OpenAlex.
- Precision cardiovascular medicine: shifting the innovation paradigm.Frontiers in science · 2025Article
- Transcriptional response to combination antiretroviral therapy predicts side effects and novel targets.Frontiers in pharmacology · 2025Article
- Review
- Systems immunology-based drug repurposing framework to target inflammation in atherosclerosis.Nature cardiovascular research · 2023Article
- Emerging computational paradigms to address the complex role of gut microbial metabolism in cardiovascular diseases.Frontiers in cardiovascular medicine · 2022Review
- Connections for Matters of the Heart: Network Medicine in Cardiovascular Diseases.Frontiers in cardiovascular medicine · 2022Review
- Systems biology in cardiovascular disease: a multiomics approach.Nature reviews. Cardiology · 2021Review
- Genetics of Arterial-Wall-Specific Mechanisms in Atherosclerosis: Focus on Mitochondrial Mutations.Current atherosclerosis reports · 2020Review
- Cellular Mechanisms of Human Atherogenesis: Focus on Chronification of Inflammation and Mitochondrial Mutations.Frontiers in pharmacology · 2020Review
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundAntiretroviral 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.
methodsTranscriptional 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.
resultsTen 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).
conclusionsBy 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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