Identification of key upregulated genes involved in foam cell formation and the modulatory role of statin therapy

Ali Mahmoudi; Stephen L Atkin; Tannaz Jamialahmadi; Amirhossein Sahebkar

doi:10.1016/j.intimp.2023.110209

Identification of key upregulated genes involved in foam cell formation and the modulatory role of statin therapy

Int Immunopharmacol. 2023 Jun:119:110209. doi: 10.1016/j.intimp.2023.110209. Epub 2023 Apr 30.

Authors

Ali Mahmoudi¹, Stephen L Atkin², Tannaz Jamialahmadi³, Amirhossein Sahebkar⁴

Affiliations

¹ Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 9177899191, Iran.
² School of Postgraduate Studies and Research, RCSI Medical University of Bahrain, Busaiteen 15503, Bahrain.
³ Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
⁴ Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, The University of Western Australia, Perth, Australia; Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: sahebkara@mums.ac.ir.

PMID: 37130442
DOI: 10.1016/j.intimp.2023.110209

Abstract

Background: We aimed to investigate the possible effect of statins on important genes/proteins involved in foam cell formation.

Methods: The gene expression profile of the GSE9874, GSE54666, and GSE7138from the Omnibus database were usedto identify genes involved in foam cell formation. The protein-protein interaction (PPI) network and MCODE analysis of the intersection of three databases were analyzed. We used molecular docking analysis to investigate the possible interaction of different statins with the overexpressed hub genes obtained from PPI analysis.

Results: The intersection among the three datasets showed 54 upregulated and 26 down-regulated genes. The most critical overexpressed genes/proteins obtained as hub genes included: G6PD, NPC1, ABCA1, ABCG1, PGD, PLIN2, PPAP2B, and TXNRD1 based on PPI analysis. Functional enrichment analysis of 81 intersection DEGs at the biological process level focusing on the cholesterol metabolic process, secondary alcohol biosynthetic process and the cholesterol biosynthetic process. Under cellular components, the analysis confirmed that these 81 intersection DEGs were mainly applied in endoplasmic reticulum membrane, lysosome and lytic vacuole. The molecular functions were identified as sterol binding, oxidoreductase activity and NADP binding. The molecular docking showed that all statins appear to affect important protein targets overexpressed in foam cell formation. However, lipophilic statins, especially pitavastatin and lovastatin, had a greater effect than hydrophilic statins. The most significant protein target of all the overexpressed genes interacting with all statin types was ABCA1.

Conclusion: The effect of lipophilic statins was shown for several critical proteins in foam cell formation.

Keywords: Foam cell; Gene ontology; KEGG; Molecular docking; PPI network; Statins.

MeSH terms

Biomarkers, Tumor / genetics
Cholesterol
Computational Biology
Foam Cells
Gene Expression Profiling*
Hydroxymethylglutaryl-CoA Reductase Inhibitors* / pharmacology
Molecular Docking Simulation

Substances

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Biomarkers, Tumor
Cholesterol