Determining the biomarkers and pathogenesis of myocardial infarction combined with ankylosing spondylitis via a systems biology approach

Abstract

Ankylosing spondylitis (AS) is linked to an increased prevalence of myocardial infarction (MI). However, research dedicated to elucidating the pathogenesis of AS-MI is lacking. In this study, we explored the biomarkers for enhancing the diagnostic and therapeutic efficiency of AS-MI. Datasets were obtained from the Gene Expression Omnibus database. We employed weighted gene co-expression network analysis and machine learning models to screen hub genes. A receiver operating characteristic curve and a nomogram were designed to assess diagnostic accuracy. Gene set enrichment analysis was conducted to reveal the potential function of hub genes. Immune infiltration analysis indicated the correlation between hub genes and the immune landscape. Subsequently, we performed single-cell analysis to identify the expression and subcellular localization of hub genes. We further constructed a transcription factor (TF)-microRNA (miRNA) regulatory network. Finally, drug prediction and molecular docking were performed. S100A12 and MCEMP1 were identified as hub genes, which were correlated with immune-related biological processes. They exhibited high diagnostic value and were predominantly expressed in myeloid cells. Furthermore, 24 TFs and 9 miRNA were associated with these hub genes. Enzastaurin, meglitinide, and nifedipine were predicted as potential therapeutic agents. Our study indicates that S100A12 and MCEMP1 exhibit significant potential as biomarkers and therapeutic targets for AS-MI, offering novel insights into the underlying etiology of this condition.

Keywords

myocardial infarction / ankylosing spondylitis / inflammation / bioinformatics analysis

References

[1] Cai S, Zhao M, Zhou B, Yoshii A, Bugg D, Villet O, Sahu A, Olson GS, Davis J, Tian R. Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction. J Clin Invest 2023; 133(4): e159498

[2] Salari N, Morddarvanjoghi F, Abdolmaleki A, Rasoulpoor S, Khaleghi AA, Hezarkhani LA, Shohaimi S, Mohammadi M. The global prevalence of myocardial infarction: a systematic review and meta-analysis. BMC Cardiovasc Disord 2023; 23(1): 206

[3] Hu D, Li R, Li Y, Wang M, Wang L, Wang S, Cheng H, Zhang Q, Fu C, Qian Z, Wei Q. Inflammation-targeted nanomedicines alleviate oxidative stress and reprogram macrophages polarization for myocardial infarction treatment. Adv Sci (Weinh) 2024; 11(21): e2308910

[4] Pluijmert NJ, de Jong RCM, de Vries MR, Pettersson K, Atsma DE, Jukema JW, Quax PHA. Phosphorylcholine antibodies restrict infarct size and left ventricular remodelling by attenuating the unreperfused post-ischaemic inflammatory response. J Cell Mol Med 2021; 25(16): 7772–7782

[5] Ranganathan V, Gracey E, Brown MA, Inman RD, Haroon N. Pathogenesis of ankylosing spondylitis—recent advances and future directions. Nat Rev Rheumatol 2017; 13(6): 359–367

[6] van der Linden S, van der Heijde D. Clinical aspects, outcome assessment, and management of ankylosing spondylitis and postenteric reactive arthritis. Curr Opin Rheumatol 2000; 12(4): 263–268

[7] Hwang MC, Ridley L, Reveille JD. Ankylosing spondylitis risk factors: a systematic literature review. Clin Rheumatol 2021; 40(8): 3079–3093

[8] Peters MJ, Visman I, Nielen MM, Van Dillen N, Verheij RA, van der Horst-Bruinsma IE, Dijkmans BA, Nurmohamed MT. Ankylosing spondylitis: a risk factor for myocardial infarction. Ann Rheum Dis 2010; 69(3): 579–581

[9] Mavrogeni S, Servos G, Smerla R, Markousis-Mavrogenis G, Grigoriadou G, Kolovou G, Papadopoulos G. Cardiovascular involvement in pediatric systemic autoimmune diseases: the emerging role of noninvasive cardiovascular imaging. Inflamm Allergy Drug Targets 2015; 13(6): 371–381

[10] Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 2018; 36(5): 411–420

[11] Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31(2): 455–461

[12] Kim RB, Kim JR, Hwang JY. Epidemiology of myocardial infarction in Korea: hospitalization incidence, prevalence, and mortality. Epidemiol Health 2022; 44: e2022057

[13] Su Z, Zou Z, Hay SI, Liu Y, Li S, Chen H, Naghavi M, Zimmerman MS, Martin GR, Wilner LB, Sable CA, Murray CJL, Kassebaum NJ, Patton GC, Zhang H. Global, regional, and national time trends in mortality for congenital heart disease, 1990–2019: an age-period-cohort analysis for the Global Burden of Disease 2019 study. EClinicalMedicine 2022; 43: 101249

[14] Xiao ZX, Miller JS, Zheng SG. An updated advance of autoantibodies in autoimmune diseases. Autoimmun Rev 2021; 20(2): 102743

[15] Sitia S, Atzeni F, Sarzi-Puttini P, Di Bello V, Tomasoni L, Delfino L, Antonini-Canterin F, Di Salvo G, De Gennaro Colonna V, La Carrubba S, Carerj S, Turiel M. Cardiovascular involvement in systemic autoimmune diseases. Autoimmun Rev 2009; 8(4): 281–286

[16] Papagoras C, Voulgari PV, Drosos AA. Cardiovascular disease in spondyloarthritides. Curr Vasc Pharmacol 2020; 18(5): 473–487

[17] Park CJ, Choi YJ, Kim JG, Han IB, Do Han K, Choi JM, Sohn S. Association of acute myocardial infarction with ankylosing spondylitis: a nationwide longitudinal cohort study. J Clin Neurosci 2018; 56: 34–37

[18] Blanco LP, Wang X, Carlucci PM, Torres-Ruiz JJ, Romo-Tena J, Sun HW, Hafner M, Kaplan MJ. RNA externalized by neutrophil extracellular traps promotes inflammatory pathways in endothelial cells. Arthritis Rheumatol 2021; 73(12): 2282–2292

[19] Rengarajan A, Goldblatt HE, Beebe DJ, Virumbrales-Muñoz M, Boeldt DS. Immune cells and inflammatory mediators cause endothelial dysfunction in a vascular microphysiological system. Lab Chip 2024; 24(6): 1808–1820

[20] Zhu M, Goetsch SC, Wang Z, Luo R, Hill JA, Schneider J, Morris SM Jr, Liu ZP. FoxO4 promotes early inflammatory response upon myocardial infarction via endothelial Arg1. Circ Res 2015; 117(11): 967–977

[21] Ambler WG, Kaplan MJ. Vascular damage in systemic lupus erythematosus. Nat Rev Nephrol 2024; 20(4): 251–265

[22] Tong R, Jia T, Shi R, Yan F. Inhibition of microRNA-15 protects H9c2 cells against CVB3-induced myocardial injury by targeting NLRX1 to regulate the NLRP3 inflammasome. Cell Mol Biol Lett 2020; 25(1): 6

[23] Prabhu SD, Frangogiannis NG. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ Res 2016; 119(1): 91–112

[24] Broch K, Anstensrud AK, Woxholt S, Sharma K, Tøllefsen IM, Bendz B, Aakhus S, Ueland T, Amundsen BH, Damås JK, Berg ES, Bjørkelund E, Bendz C, Hopp E, Kleveland O, Stensæth KH, Opdahl A, Kløw NE, Seljeflot I, Andersen G, Wiseth R, Aukrust P, Gullestad L. Randomized trial of interleukin-6 receptor inhibition in patients with acute ST-segment elevation myocardial infarction. J Am Coll Cardiol 2021; 77(15): 1845–1855

[25] Chen R, Zhao H, Yan H. Long-term management of patients with myocardial infarction: an updated review. Cardiol Discov 2022; 2(4): 241–262

[26] Wang L, Wang Y, Jiang Y, Chen M, Li Z, Wang K, Luo C, Ning N, Zeng J, Zhou Z, Song Y, Yang F, Huang SS, Lin Y. Tetrahedral framework nuclear acids can regulate interleukin-17 pathway to alleviate inflammation and inhibit heterotopic ossification in ankylosing spondylitis. ACS Nano 2023; 17(23): 24187–24199

[27] Li Y, He Y, Chen S, Wang Q, Yang Y, Shen D, Ma J, Wen Z, Ning S, Chen H. S100A12 as biomarker of disease severity and prognosis in patients with idiopathic pulmonary fibrosis. Front Immunol 2022; 13: 810338

[28] Gonzalez LL, Garrie K, Turner MD. Role of S100 proteins in health and disease. Biochim Biophys Acta Mol Cell Res 2020; 1867(6): 118677

[29] Foell D, Kane D, Bresnihan B, Vogl T, Nacken W, Sorg C, Fitzgerald O, Roth J. Expression of the pro-inflammatory protein S100A12 (EN-RAGE) in rheumatoid and psoriatic arthritis. Br J Rheumatol 2003; 42(11): 1383–1389

[30] Zhang X, Cheng M, Gao N, Li Y, Yan C, Tian X, Liu D, Qiu M, Wang X, Luan B, Deng J, Wang S, Tian H, Wang G, Ma X, Stone GW, Han Y. Utility of S100A12 as an early biomarker in patients with ST-segment elevation myocardial infarction. Front Cardiovasc Med 2021; 8: 747511

[31] Li K, Wang SW, Li Y, Martin RE, Li L, Lu M, Lamhamedi-Cherradi SE, Hu G, Demissie-Sanders S, Zheng J, Chung F, Oates T, Yao Z. Identification and expression of a new type II transmembrane protein in human mast cells. Genomics 2005; 86(1): 68–75

[32] Raman K, O’Donnell MJ, Czlonkowska A, Duarte YC, Lopez-Jaramillo P, Peñaherrera E, Sharma M, Shoamanesh A, Skowronska M, Yusuf S, Paré G. Peripheral blood MCEMP1 gene expression as a biomarker for stroke prognosis. Stroke 2016; 47(3): 652–658

[33] Decock J, Hendrickx W, Thirkettle S, Gutiérrez-Fernández A, Robinson SD, Edwards DR. Pleiotropic functions of the tumor- and metastasis-suppressing matrix metalloproteinase-8 in mammary cancer in MMTV-PyMT transgenic mice. Breast Cancer Res 2015; 17(1): 38

[34] Oeckinghaus A, Ghosh S. The NF-κB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 2009; 1(4): a000034

[35] Ma Y, Yabluchanskiy A, Lindsey ML. Neutrophil roles in left ventricular remodeling following myocardial infarction. Fibrogenesis Tissue Repair 2013; 6(1): 11

[36] Ge L, Zhou X, Ji WJ, Lu RY, Zhang Y, Zhang YD, Ma YQ, Zhao JH, Li YM. Neutrophil extracellular traps in ischemia-reperfusion injury-induced myocardial no-reflow: therapeutic potential of DNase-based reperfusion strategy. Am J Physiol Heart Circ Physiol 2015; 308(5): H500–H509

[37] Rosenzweig HL, Vance EE, Asare-Konadu K, Koney KV, Lee EJ, Deodhar AA, Sen R, Caplan L, Napier RJ. Card9/neutrophil signalling axis promotes IL-17A-mediated ankylosing spondylitis. Ann Rheum Dis 2024; 83(2): 214–222

[38] Peet C, Ivetic A, Bromage DI, Shah AM. Cardiac monocytes and macrophages after myocardial infarction. Cardiovasc Res 2020; 116(6): 1101–1112

[39] Pietzsch J, Hoppmann S. Human S100A12: a novel key player in inflammation. Amino Acids 2009; 36(3): 381–389

[40] Chen JX, Xu X, Zhang S. Silence of long noncoding RNA NEAT1 exerts suppressive effects on immunity during sepsis by promoting microRNA-125-dependent MCEMP1 downregulation. IUBMB Life 2019; 71(7): 956–968

[41] Xia P, Ji X, Yan L, Lian S, Chen Z, Luo Y. Roles of S100A8, S100A9 and S100A12 in infection, inflammation and immunity. Immunology 2024; 171(3): 365–376

[42] Oesterle A, Bowman MA. S100A12 and the S100/Calgranulins: emerging biomarkers for atherosclerosis and possibly therapeutic targets. Arterioscler Thromb Vasc Biol 2015; 35(12): 2496–2507

[43] Pakkir Maideen NM, Manavalan G, Balasubramanian K. Drug interactions of meglitinide antidiabetics involving CYP enzymes and OATP1B1 transporter. Ther Adv Endocrinol Metab 2018; 9(8): 259–268

[44] Roberts R, Jaffe AS, Henry PD, Sobel BE. Nifedipine and acute myocardial infarction. Herz 1981; 6(2): 90–97

[45] Polisety A, Misra G, Rajawat J, Katiyar A, Singh H, Bhatt AN. Therapeutic natural compounds Enzastaurin and Palbociclib inhibit MASTL kinase activity preventing breast cancer cell proliferation. Med Oncol 2022; 39(5): 100

[46] Shimokawa T, Seike M, Soeno C, Uesaka H, Miyanaga A, Mizutani H, Kitamura K, Minegishi Y, Noro R, Okano T, Yoshimura A, Gemma A. Enzastaurin has anti-tumour effects in lung cancers with overexpressed JAK pathway molecules. Br J Cancer 2012; 106(5): 867–875

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