For almost a century, many have considered lipids as the sine qua non of atherosclerosis. However, in 1856 Rudolf Virchow introduced a theory that inflammation is the driving force of atherogenesis. Recruitment of blood leukocytes to the injured vascular endothelium characterizes the initiation and progression of atherosclerosis and involves many inflammatory mediators, modulated by cells of both innate and adaptive immunity. The pro-inflammatory cytokine, interferon (IFN)-γ derived from T cells, is vital for both innate and adaptive immunity and is also expressed at high levels in atherosclerotic lesions. As such, IFN-γ plays a crucial role in the pathology of atherosclerosis through activation of signal transducer and activator of transcription STAT1.Our study indeed provides evidence that in HMECs STAT1 coordinates a platform for cross-talk between IFNγ and TLR4, and identifies a STAT1-dependent gene signature that reflects a pro-atherogenic state in coronary artery disease (CAD) and carotid atherosclerosis. Taken together, our data indicate that in the presence of appropriate stimuli, HMECs are highly responsive and consistently express Cxcl9. HMECs may therefore provide a better model for in vitro studies of atherosclerosis.

Atherosclerosis, biomarkers,chemokine, Cxcl9

Mozaffarian, D.; Benjamin, E.J.; Go, A.S.; Arnett, D.K.; Blaha, M.J.; Cushman, M.D.; Das, S.R.; De Ferranti, S.; Cushman, M.; Despr’s, J.P.; et al. Executive Summary: Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 2016, 133, 447–454. [CrossRef] [PubMed]

Benjamin, E.J.; Virani, S.S.; Callaway, C.W.; Chamberlain, A.M.; Chang, A.R.; Cheng, S.; Chiuve, S.E.; Cushman, M.; Delling, F.N.; Deo, R. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation 2018, 137, e67–e492. [CrossRef] [PubMed]

Day A., Jameson Z., Hyde C., Simbi B., Fowkes R.C-Type Natriuretic Peptide (CNP) Inhibition of Interferon-γ-Mediated Gene Expression in Human Endothelial Cells In Vitro. Biosensors (Basel) . 2018 Sep 14;8(3):86. doi: 10.3390/bios8030086.

Roberta D. R., MD; Leistner D. M., MD; Sophia M. Reis, MD; et al. Coronary Atherosclerotic Plaque Characteristics and Cardiovascular Risk Factors.Circ J. 2017 Jul 25;81(8):1165-1173. doi: 0.1253/circj.CJ-17-0054. Epub 2017 Apr 14.

Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006; 6:508-19; doi.org/10.1038/nri1882

Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–843.

MartynaPlens-Galaska, MalgorzataSzelag, Hans A R Bluyssen; et al. 1Genome-Wide Inhibition of Pro-atherogenic Gene Expression by Multi-STAT Targeting Compounds as a Novel Treatment Strategy of CVDs. Front Immunol .FrontImmunol. 2018 Sep 19;9:2141. doi: 10.3389/fimmu.2018.02141. eCollection 2018.

Haverkate F, Thompson SG, Pyke SD, et al. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet. 1997; 349:462–466.

Pleunie van den Borne, et al. The Multifaceted Functions of CXCL10 in Cardiovascular Disease. BiomedResInt. 2014;2014:893106. doi: 10.1155/2014/893106. Epub 2014 Apr 23.

Hans A. R. Bluyssen, et al. A Positive Feedback Amplifier Circuit That Regulates Interferon (IFN)-Stimulated Gene Expression and Controls Type I and Type II IFN Responses. Front Immunol. 2018 May 8;9:1135. doi: 10.3389/fimmu.2018.01135. eCollection 2018.

D. D. Taub, “Chemokine-leukocyte interactions. The voodoo that they do so well,” Cytokine & Growth Factor Reviews, vol. 7, no. 4, pp. 355–376, 1996.

E. J. Fernandez and E. Lolis, “Structure, function, and inhibition of chemokines,” Annual Review of Pharmacology and Toxicology, vol. 42, pp. 469–499, 2002.

P. van den Borne, P. H. A. Quax, I. E. Hoefer, and G. Pasterkamp, “The multifaceted functions of CXCL10 in cardiovascular disease,” BioMed Research International, vol. 2014, Article ID 893106, 11 pages, 2014.

Giovanny Aguilera-Durán, Antonio Romo-Mancillas. Computational Study of C-X-C Chemokine Receptor (CXCR)3 Binding with Its Natural Agonists Chemokine (C-X-C Motif) Ligand (CXCL)9, 10 and 11 and with Synthetic Antagonists: Insights of Receptor Activation towards Drug Design for Vitiligo.Molecules. 2020 Sep 25;25(19):4413. doi: 10.3390/molecules25194413.

Qin S, Rottman JB, Myers P, et al: The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest 101: 746-754, 1998.

Cole KE, Strick CA, Paradis TJ, et al: Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3. J Exp Med 187: 2009‑2021, 1998.

Clark-Lewis I, Mattioli I, Gong JH and Loetscher P: Structure-function relationship between the human chemokine receptor CXCR3 and its ligands. J BiolChem 278: 289-295, 2003.

J. R. Groom and A. D. Luster, “CXCR3 ligands: redundant, collaborative and antagonistic functions,” Immunology and Cell Biology, vol. 89, no. 2, pp. 207–215, 2011.

Alain Tedgui, ZiadMallat. Cytokines in atherosclerosis: pathogenic and regulatory pathways. PhysiolRev. 2006 Apr;86(2):515-81. doi: 10.1152/physrev.00024.2005.

Hans A. R. Bluyssen, et al. STAT1 as a novel therapeutical target in pro-atherogenic signal integration of IFNγ, TLR4 and IL-6 in vascular disease. Cytokine Growth Factor Rev. 2011 Aug;22(4):211-9. doi: 10.1016/j.cytogfr.2011.06.003.

Hans A. R. Bluyssen, et al. STAT1-dependent signal integration between IFNgamma and TLR4 in vascular cells reflect pro-atherogenic responses in human atherosclerosis. PloS one. 2014;9:e113318. Published online 2014 Dec 5. doi: 10.1371/journal.pone.0113318.

Pohjanvirta T., et al. Evaluation of various housekeeping genes for their applicability for normalization of mRNA expression in dioxin-treated rats.ChemBiol Interact. 2006 Mar 25;160(2):134-49. doi: 10.1016/j.cbi.2006.01.001. Epub 2006 Feb8.