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J Pediatr Infect Dis 2024; 19(01): 039-051
DOI: 10.1055/s-0043-1777093
Original Article

Identification of a Novel lncRNA in Diagnosis of Sepsis-Induced Cardiomyopathy Using a Comprehensive Analysis of lncRNA-mRNA Network

Yue Li
1   Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
,
Zhongqiang Liu
1   Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
,
Ruixiang Tang
2   Key Laboratory of Bioresources and Eco-Environment (MOE), College of Life Sciences, Sichuan University, Chengdu, Sichuan, People's Republic of China
,
Maoyun Deng
1   Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
,
Jinlin Wu
1   Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
,
Guoyan Lu
1   Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
,
Yifei Li 
1   Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
,
Zhenxin Fan
2   Key Laboratory of Bioresources and Eco-Environment (MOE), College of Life Sciences, Sichuan University, Chengdu, Sichuan, People's Republic of China
› Author Affiliations Funding This work was supported by grants from the Technology Project of Sichuan Province of China (2021YFQ0061) and the National Natural Science Foundation of China (82270249). The funding did not participate in the design of the study and collection, analysis, and interpretation of data or in writing the manuscript.
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Abstract

Objective Long noncoding RNAs (lncRNAs) have been implicated in various biological processes, particularly in the regulation of inflammatory responses and myocardial injuries. Notably, the role of lncRNAs in sepsis-induced cardiomyopathy (SIC) has been highlighted. However, a comprehensive analysis investigating the specific circulating lncRNAs associated with SIC has yet to be conducted. Therefore, we conducted a study involving samples from healthy controls, sepsis patients without myocardial injuries, individuals with cardiac dysfunction following heart surgery, and those with SIC, aiming to identify the distinct lncRNAs involved in SIC.

Methods A total of 12 blood samples were collected, including healthy controls, sepsis patients without myocardial injuries, patients with cardiac surgery-related myocardial injuries, and patients with SIC, who were aged from 10 to 22 months. Transcriptome sequencing was conducted to identify differentially expressed (DE) lncRNAs and mRNAs. Venn plots were employed to identify the DE RNAs specific to SIC. Subsequently, enrichment analyses were performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms. A coexpression network between lncRNAs and mRNAs was constructed, focusing on protein–protein interaction features. Then, further validation had been done in a consecutive larger cohort.

Results We identified independent DE mRNAs and lncRNAs specific to SIC patients. The analysis of DE mRNAs revealed that immune activation, particularly innate immune activity, was the primary distinction between sepsis with or without myocardial injuries. Furthermore, cytokine production, particularly interleukin-1 secretion, played a significant role in inducing SIC. The expression profiles of DE lncRNAs showed considerable enrichment in shared topics with mRNAs. Subsequently, we identified lncRNAs targeting the DE mRNAs, many of which were involved in immune responses and cytokine production. We established a coexpression network between lncRNAs and mRNAs, leading to the discovery of a novel lncRNA (TCONS_00136255). Finally, we successfully validated TCONS_00136255, demonstrating its acceptable diagnostic accuracy and its role in regulating major molecular processes involved in SIC.

Conclusion lncRNAs actively participate in the significant biological changes associated with immune responses in sepsis-induced myocardial injuries. These lncRNAs interact with mRNAs to modulate inflammation activity and cytokine production. Notably, the identification of the novel lncRNA (TCONS_00136255) highlights its crucial regulatory role in SIC.

Keywords

lncRNA - sepsis - cardiomyopathy - myocardial injuries - TCONS_00136255

Ethical Approval and Consent to Participate

This study was approved by the Ethics Committee of West China Second Hospital of Sichuan University (2014034). Informed consent from all the patient's parents was obtained, including the patient's clinical and imaging details in the manuscript for the purpose of publication.


Consent for Publication

Not Applicable.


Availability of Data and Material

All the data are presented in the manuscript. Other datasets used in this study are available from the corresponding author upon reasonable request.


Authors' Contributions

Y.L., Z.L., R.T., M.D., J.W., G.L., and Y.L. collected the clinical data. Y.L. and Y.L. reviewed the literature and contributed to manuscript drafting; R.T. and Z.F. performed the sequencing analysis. Y.L. and G.L. conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content. Y.L. and Z.F. were responsible for the revision of the manuscript for important intellectual content; all authors issued final approval for the version to be submitted.




Publication History

Received: 12 June 2023

Accepted: 17 October 2023

Article published online:
11 December 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Fleischmann-Struzek C, Goldfarb DM, Schlattmann P, Schlapbach LJ, Reinhart K, Kissoon N. The global burden of paediatric and neonatal sepsis: a systematic review. Lancet Respir Med 2018; 6 (03) 223-230
    CrossrefPubMedGoogle Scholar
  • 2 Singer M, Deutschman CS, Seymour CW. et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315 (08) 801-810
    Google Scholar
  • 3 Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013; 369 (09) 840-851
    CrossrefPubMedGoogle Scholar
  • 4 Ye W, Liu X, Bai Y. et al. Sepsis activates the TLR4/MyD88 pathway in Schwann cells to promote infiltration of macrophages, thereby impeding neuromuscular function. Shock 2021; 55 (01) 90-99
    CrossrefPubMedGoogle Scholar
  • 5 Kong W, Kang K, Gao Y. et al. GTS-21 protected against LPS-induced sepsis myocardial injury in mice through α7nAChR. Inflammation 2018; 41 (03) 1073-1083
    CrossrefPubMedGoogle Scholar
  • 6 Tang Y, He X. Long non-coding RNAs in nasopharyngeal carcinoma: biological functions and clinical applications. Mol Cell Biochem 2021; 476 (09) 3537-3550
    CrossrefPubMedGoogle Scholar
  • 7 Gao F, Cai Y, Kapranov P, Xu D. Reverse-genetics studies of lncRNAs-what we have learnt and paths forward. Genome Biol 2020; 21 (01) 93
    CrossrefPubMedGoogle Scholar
  • 8 Thygesen K, Alpert JS, Jaffe AS. et al; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction. Fourth universal definition of myocardial infarction (2018). Circulation 2018; 138 (20) e618-e651
    CrossrefPubMedGoogle Scholar
  • 9 Zheng Y-L, Song G, Guo J-B. et al. Interactions among lncRNA/circRNA, miRNA, and mRNA in musculoskeletal degenerative diseases. Front Cell Dev Biol 2021; 9: 753931
    CrossrefPubMedGoogle Scholar
  • 10 Xie L, Zhang Q, Mao J, Zhang J, Li L. The roles of lncRNA in myocardial infarction: molecular mechanisms, diagnosis biomarkers, and therapeutic perspectives. Front Cell Dev Biol 2021; 9: 680713
    CrossrefPubMedGoogle Scholar
  • 11 Shen Y, Peng X, Shen C. Identification and validation of immune-related lncRNA prognostic signature for breast cancer. Genomics 2020; 112 (03) 2640-2646
    CrossrefPubMedGoogle Scholar
  • 12 Xie J, Li H, Li S, Li J, Li Y. Molecular mechanism of sevoflurane preconditioning based on whole-transcriptome sequencing of lipopolysaccharide-induced cardiac dysfunction in mice. J Cardiovasc Pharmacol 2022; 79 (06) 846-857
    CrossrefPubMedGoogle Scholar
  • 13 Wu H, Liu J, Li W, Liu G, Li Z. LncRNA-HOTAIR promotes TNF-α production in cardiomyocytes of LPS-induced sepsis mice by activating NF-κB pathway. Biochem Biophys Res Commun 2016; 471 (01) 240-246
    CrossrefPubMedGoogle Scholar
  • 14 Zhuang YT, Xu DY, Wang GY, Sun JL, Huang Y, Wang SZ. IL-6 induced lncRNA MALAT1 enhances TNF-α expression in LPS-induced septic cardiomyocytes via activation of SAA3. Eur Rev Med Pharmacol Sci 2017; 21 (02) 302-309
    PubMedGoogle Scholar
  • 15 Y-Hassan S, Settergren M, Henareh L. Sepsis-induced myocardial depression and takotsubo syndrome. Acute Card Care 2014; 16 (03) 102-109
    CrossrefPubMedGoogle Scholar
  • 16 Li L, Peng X, Guo L, Zhao Y, Cheng Q. Sepsis causes heart injury through endoplasmic reticulum stress-mediated apoptosis signaling pathway. Int J Clin Exp Pathol 2020; 13 (05) 964-971
    PubMedGoogle Scholar
  • 17 Eisenberg MA, Green-Hopkins I, Alexander ME, Chiang VW. Cardiac troponin T as a screening test for myocarditis in children. Pediatr Emerg Care 2012; 28 (11) 1173-1178
    CrossrefPubMedGoogle Scholar
  • 18 Luo Y, Xu H, Yang Z. et al. Long non-coding RNA MALAT1 silencing elevates microRNA-26a-5p to ameliorate myocardial injury in sepsis by reducing regulator of calcineurin 2. Arch Biochem Biophys 2022; 715: 109047
    CrossrefPubMedGoogle Scholar
  • 19 McDonel P, Guttman M. Approaches for understanding the mechanisms of long noncoding RNA regulation of gene expression. Cold Spring Harb Perspect Biol 2019; 11 (12) a032151
    CrossrefPubMedGoogle Scholar
  • 20 Wang X, Li X-L, Qin L-J. The lncRNA XIST/miR-150-5p/c-Fos axis regulates sepsis-induced myocardial injury via TXNIP-modulated pyroptosis. Lab Invest 2021; 101 (09) 1118-1129
    CrossrefPubMedGoogle Scholar
  • 21 Wang SM, Liu GQ, Xian HB, Si JL, Qi SX, Yu YP. LncRNA NEAT1 alleviates sepsis-induced myocardial injury by regulating the TLR2/NF-κB signaling pathway. Eur Rev Med Pharmacol Sci 2019; 23 (11) 4898-4907
    PubMedGoogle Scholar
  • 22 Wang J, Xin S, Yang R, Jiang J, Qiao Y. Knockdown of lncRNA LUCAT1 attenuates sepsis–induced myocardial cell injury by sponging miR-642a. Mamm Genome 2021; 32 (06) 457-465
    CrossrefPubMedGoogle Scholar
  • 23 Zhao J, Han X, Xue L, Zhu K, Liu H, Xie A. Association of TLR4 gene polymorphisms with sporadic Parkinson's disease in a Han Chinese population. Neurol Sci 2015; 36 (09) 1659-1665
    CrossrefPubMedGoogle Scholar
  • 24 Wang Z, Chen W, Li Y. et al. Reduning injection and its effective constituent luteoloside protect against sepsis partly via inhibition of HMGB1/TLR4/NF-κB/MAPKs signaling pathways. J Ethnopharmacol 2021; 270: 113783
    CrossrefPubMedGoogle Scholar
  • 25 Djuric O, Andjelkovic M, Vreca M. et al. Genetic variants in TNFA, LTA, TLR2 and TLR4 genes and risk of sepsis in patients with severe trauma: nested case-control study in a level-1 trauma centre in SERBIA. Injury 2021; 52 (03) 419-425
    CrossrefPubMedGoogle Scholar
  • 26 Chen T, Zhu C, Ye C. LncRNA CYTOR attenuates sepsis-induced myocardial injury via regulating miR-24/XIAP. Cell Biochem Funct 2020; 38 (07) 976-985
    CrossrefPubMedGoogle Scholar
  • 27 Shan B, Li J-Y, Liu Y-J, Tang X-B, Zhou Z, Luo L-X. LncRNA H19 inhibits the progression of sepsis-induced myocardial injury via regulation of the miR-93–5p/SORBS2 axis. Inflammation 2021; 44 (01) 344-357
    CrossrefPubMedGoogle Scholar
  • 28 Liu J-J, Li Y, Yang M-S, Chen R, Cen C-Q. SP1-induced ZFAS1 aggravates sepsis-induced cardiac dysfunction via miR-590-3p/NLRP3-mediated autophagy and pyroptosis. Arch Biochem Biophys 2020; 695: 108611
    CrossrefPubMedGoogle Scholar
  • 29 Martin L, Derwall M, Al Zoubi S. et al. The septic heart: current understanding of molecular mechanisms and clinical implications. Chest 2019; 155 (02) 427-437
    CrossrefPubMedGoogle Scholar
  • 30 Hoffman M, Kyriazis ID, Lucchese AM. et al. Myocardial strain and cardiac output are preferable measurements for cardiac dysfunction and can predict mortality in septic mice. J Am Heart Assoc 2019; 8 (10) e012260
    CrossrefPubMedGoogle Scholar
  • 31 Zhang W, Xu X, Kao R. et al. Cardiac fibroblasts contribute to myocardial dysfunction in mice with sepsis: the role of NLRP3 inflammasome activation. PLoS One 2014; 9 (09) e107639
    CrossrefPubMedGoogle Scholar
  • 32 Busch K, Kny M, Huang N. et al. Inhibition of the NLRP3/IL-1β axis protects against sepsis-induced cardiomyopathy. J Cachexia Sarcopenia Muscle 2021; 12 (06) 1653-1668
    CrossrefPubMedGoogle Scholar
  • 33 Heijman J, Muna AP, Veleva T. et al. Atrial myocyte NLRP3/CaMKII nexus forms a substrate for postoperative atrial fibrillation. Circ Res 2020; 127 (08) 1036-1055
    CrossrefPubMedGoogle Scholar