Alterations in Genes Associated with Cytosolic RNA Sensing in Whole Blood Are Associated with Coronary Microvascular Disease in SLE

Overview

Journal Sci Rep

Date 2025 Jan 19

PMID 39828802

Authors

Lihong Huo

Arati Naveen Kumar

Gantsetseg Tumurkhuu

Moumita Bose

Daniel S Berman

Daniel J Wallace

Janet Wei

Mariko Ishimori

C Noel Bairey Merz

Caroline Jefferies

Affiliations

Soon will be listed here.

Abstract

Systemic lupus erythematosus (SLE) patients are 90% women and over three times more likely to die of cardiovascular disease than women in the general population. Chest pain with no obstructive cardiac disease is associated with coronary microvascular disease (CMD), where narrowing of the small blood vessels can lead to ischemia, and frequently reported by SLE patients. Using whole blood RNA samples, we asked whether gene signatures discriminate SLE patients with coronary microvascular dysfunction (CMD) on cardiac MRI (n = 4) from those without (n = 7) and whether any signaling pathway is linked to the underlying pathobiology of SLE CMD. RNA-seq analysis revealed 143 differentially expressed (DE) genes between the SLE and healthy control (HC) groups, with virus defense and interferon (IFN) signaling being the key pathways identified as enriched in SLE as expected. We next conducted a comparative analysis of genes differentially expressed in SLE-CMD and SLE-non-CMD relative to HC samples. Our analysis highlighted differences in IFN signaling, RNA sensing and ADP-ribosylation pathways between SLE-CMD and SLE-non-CMD. This is the first study to investigate possible gene signatures associating with CMD in SLE, and our data strongly suggests that distinct molecular mechanisms underly vascular changes in CMD and non-CMD involvement in SLE.

References

Xing J, Zhang A, Du Y, Fang M, Minze L, Liu Y . Identification of poly(ADP-ribose) polymerase 9 (PARP9) as a noncanonical sensor for RNA virus in dendritic cells. Nat Commun. 2021; 12(1):2681. PMC: 8113569. DOI: 10.1038/s41467-021-23003-4. View

Hung O, Lee S, Eshtehardi P, Samady H . Novel biomarkers of coronary microvascular disease. Future Cardiol. 2016; 12(4):497-509. PMC: 5941701. DOI: 10.2217/fca-2016-0012. View

Weckerle C, Franek B, Kelly J, Kumabe M, Mikolaitis R, Green S . Network analysis of associations between serum interferon-α activity, autoantibodies, and clinical features in systemic lupus erythematosus. Arthritis Rheum. 2010; 63(4):1044-53. PMC: 3068224. DOI: 10.1002/art.30187. View

Manchanda A, Kwan A, Ishimori M, Thomson L, Li D, Berman D . Coronary Microvascular Dysfunction in Patients With Systemic Lupus Erythematosus and Chest Pain. Front Cardiovasc Med. 2022; 9:867155. PMC: 9053571. DOI: 10.3389/fcvm.2022.867155. View

Caprara G, Prosperini E, Piccolo V, Sigismondo G, Melacarne A, Cuomo A . PARP14 Controls the Nuclear Accumulation of a Subset of Type I IFN-Inducible Proteins. J Immunol. 2018; 200(7):2439-2454. DOI: 10.4049/jimmunol.1701117. View

Matsumoto K, Obana M, Kobayashi A, Kihara M, Shioi G, Miyagawa S . Blockade of NKG2D/NKG2D ligand interaction attenuated cardiac remodelling after myocardial infarction. Cardiovasc Res. 2018; 115(4):765-775. DOI: 10.1093/cvr/cvy254. View

Grunewald M, Chen Y, Kuny C, Maejima T, Lease R, Ferraris D . The coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression. PLoS Pathog. 2019; 15(5):e1007756. PMC: 6521996. DOI: 10.1371/journal.ppat.1007756. View

Asdonk T, Motz I, Werner N, Coch C, Barchet W, Hartmann G . Endothelial RIG-I activation impairs endothelial function. Biochem Biophys Res Commun. 2012; 420(1):66-71. DOI: 10.1016/j.bbrc.2012.02.116. View

Catalina M, Bachali P, Geraci N, Grammer A, Lipsky P . Gene expression analysis delineates the potential roles of multiple interferons in systemic lupus erythematosus. Commun Biol. 2019; 2:140. PMC: 6478921. DOI: 10.1038/s42003-019-0382-x. View

10.

Taqueti V, Di Carli M . Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the-Art Review. J Am Coll Cardiol. 2018; 72(21):2625-2641. PMC: 6296779. DOI: 10.1016/j.jacc.2018.09.042. View

11.

Ulgen E, Ozisik O, Sezerman O . pathfindR: An R Package for Comprehensive Identification of Enriched Pathways in Omics Data Through Active Subnetworks. Front Genet. 2019; 10:858. PMC: 6773876. DOI: 10.3389/fgene.2019.00858. View

12.

Handy D, Castro R, Loscalzo J . Epigenetic modifications: basic mechanisms and role in cardiovascular disease. Circulation. 2011; 123(19):2145-56. PMC: 3107542. DOI: 10.1161/CIRCULATIONAHA.110.956839. View

13.

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

14.

Hagiwara A, Montano E, Tumurkhuu G, Bose M, Bernardo M, Berman D . Reduced Left Ventricular Function on Cardiac MRI in SLE Patients Correlates with Measures of SLE Disease Activity and Inflammation. J Radiol Clin Imaging. 2024; 6(4):197-207. PMC: 10949413. DOI: 10.26502/jrci.2809088. View

15.

Baechler E, Batliwalla F, Karypis G, Gaffney P, Ortmann W, Espe K . Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003; 100(5):2610-5. PMC: 151388. DOI: 10.1073/pnas.0337679100. View

16.

Del Buono M, Montone R, Camilli M, Carbone S, Narula J, Lavie C . Coronary Microvascular Dysfunction Across the Spectrum of Cardiovascular Diseases: JACC State-of-the-Art Review. J Am Coll Cardiol. 2021; 78(13):1352-1371. PMC: 8528638. DOI: 10.1016/j.jacc.2021.07.042. View

17.

Crow M . Type I interferon in the pathogenesis of lupus. J Immunol. 2014; 192(12):5459-68. PMC: 4083591. DOI: 10.4049/jimmunol.1002795. View

18.

Caliskan M, Baycan O, Celik F, Guvenc T, Atici A, Cag Y . Coronary microvascular dysfunction is common in patients hospitalized with COVID-19 infection. Microcirculation. 2022; 29(4-5):e12757. PMC: 9115225. DOI: 10.1111/micc.12757. View

19.

Masi S, Rizzoni D, Taddei S, Widmer R, Montezano A, Luscher T . Assessment and pathophysiology of microvascular disease: recent progress and clinical implications. Eur Heart J. 2020; 42(26):2590-2604. PMC: 8266605. DOI: 10.1093/eurheartj/ehaa857. View

20.

Baksh S, Hu J, Pratt R, Dzau V, Hodgkinson C . Rig1 receptor plays a critical role in cardiac reprogramming via YY1 signaling. Am J Physiol Cell Physiol. 2023; 324(4):C843-C855. PMC: 10069961. DOI: 10.1152/ajpcell.00402.2022. View