Evaluation of altered miRNA expression pattern to predict COVID-19 severity

Srivastava, Swati; Garg, Iti; Singh, Yamini; Meena, R. C.; Ghosh, Nilabja; Kumari, Babita; Kumar, Vinay; Eslavath, Malleswara Rao; Singh, Sayar; Dogra, Vikas; Bargotya, Mona; Bhattar, Sonali; Gupta, Utkarsh; Jain, Shruti; Hussain, Hidayat; Varshney, Rajeev K.; Ganju, Lilly

doi:10.1016/j.heliyon.2023.e13388

Cited by 12 publications

(7 citation statements)

References 108 publications

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“…Multiple studies have reported the alteration in host miRNA landscape following SARSCoV2 infection[23][24][25][26][27]. miR-374b is reported to be downregulated in blood samples of COVID-19 patients[16]. In order to identify the role of miR-374b in SARS-CoV-2 mediated endothelial dysfunction, the targets of miR-374b was predicted using online web based tools like miRDB, targetscan and miRsystem, Among the predicted targets, CFLAR, ITGB1 and VEGFA, only CFLAR could satisfy our criteria with a score of 3/3 and also CFLAR was found to be the most significantly upregulated gene in gene profiling, and hence was selected for further mechanistic studies.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, this study focus on the role of miR-374b, which was found to be significantly downregulated upon profiling of SARS-CoV-2 viral protein, stimulated endothelial cells. Eventhough, miR-374b play crucial role in Endo MT and also has been reported to be downregulated in blood samples of COVID 19 patients [16], the role of miR-374b in SARS-CoV-2 mediated endothelial dysfunction remains unclear and this forms the subject matter of the present study.…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-374b regulates SARS-CoV-2 viral protein mediated endothelial to mesenchymal transition by targeting c-FLIP

Raji,

Poyyakkara,

Ramachandran

et al. 2024

Preprint

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The pathophysiological consequences of COVID-19 disease are still unclear, however, endothelial cell (EC) dysfunction has been observed to play a key role in disease progression and severity. Many reports suggests that SARS-CoV-2 mediated endothelial dysfunction is the result of intracellular signaling initiated by the binding of the spike protein to ACE2, which can modify endothelial cell phenotype. Recent reports suggests endothelial to mesenchymal transition (Endo MT) as a process heavily involved in lung fibrosis of COVID 19 patients. EndoMT is involved in many chronic and fibrotic diseases and appears to be regulated by complex molecular mechanisms and different signaling pathways, in particular microRNAs (miRNAs), which constitute a crucial mediator of EndoMT. MicroRNAs (miRNAs), small endogenous RNA molecules that regulate several physiological processes including endothelial homeostasis, and vascular diseases, can be perturbed by infecting viruses. Based on these facts, this study was designed to decipher the role of miR-374b, which was found to be significantly downregulated upon profiling of SARS-CoV-2 viral protein stimulated endothelial cells. Gene profiling of endothelial cells revealed c-FLIP (CFLAR) to be among the most significantly upregulated gene. In silico target prediction analysis using targetscan revealed c-FLIP as the major target of miR-374b. Further it was identified that miR-374b can reverse c-FLIP mRNA and protein levels in SARS-CoV-2 viral protein stimulated endothelial cells under conditions of miR-374b overexpression. Since vascular dysfunction involve, under many circumstances, loss of vascular tone due to mesenchymal transition of endothelial cells, we next checked if fibrotic events are initiated downstream of c-FLIP pathway. Further mechanistic studies involving identification of the expression pattern of mesenchymal markers in SARS-CoV-2 viral protein stimulated endothelial cells in presence or absence of miR-374b provide evidence for the important role of miR-374b in regulating SARS CoV-2 mediated EndoMT and fibrotic events downstream of c-FLIP pathway and may highlight possible new therapeutic approaches targeted at the damaged endothelium. Key words: miR-374b, SARS-CoV-2, endothelial dysfunction, EndoMT, c-FLIP.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MicroRNA-374b regulates SARS-CoV-2 viral protein mediated endothelial to mesenchymal transition by targeting c-FLIP

Raji,

Poyyakkara,

Ramachandran

et al. 2024

Preprint

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“…Recent evidence suggest that microRNA, which can influence the inflammatory cytokine response in COVID-19, can potentially infer disease severity and progression [87]. Further, microRNA could also function as possible therapeutic target in COVID-19 [88,89]. These promising findings deserve further clinical validation.…”

Section: Inflammatory Markersmentioning

confidence: 99%

Effective prognostic and clinical risk stratification in COVID‐19 using multimodality biomarkers

et al. 2023

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In acute coronavirus disease 19 (COVID‐19) patients, effective clinical risk stratification has important implications on treatment and therapeutic resource distribution. This article reviews the evidence behind a wide range of biomarkers with prognostic value in COVID‐19. Patient characteristics and co‐morbidities, such as cardiovascular and respiratory diseases, are associated with increased mortality risk. Peripheral oxygen saturation and arterial oxygenation are predictive of severe respiratory compromise, whereas risk scores such as the 4C‐score enable multi‐factorial prognostic risk estimation. Blood tests such as markers of inflammation, cardiac injury and d‐dimer and abnormalities on electrocardiogram are linked to inpatient prognosis. Of the imaging modalities, lung ultrasound and echocardiography enable the bedside assessment of prognostic abnormalities in COVID‐19. Chest radiograph (CXR) and computed tomography (CT) can inform about prognostic pulmonary pathologies, whereas cardiovascular CT detects high‐risk features such as coronary artery and aortic calcification. Dynamic changes in biomarkers, such as blood tests, CXR, CT and electrocardiogram findings, can further inform about disease severity and prognosis. Despite the vast volumes of existing evidence, several gaps exist in our understanding of COVID‐19 biomarkers. First, the pathophysiological basis on which these markers can foretell prognosis in COVID‐19 remains poorly understood. Second, certain under‐explored tests such as thoracic impedance assessment and cardiovascular magnetic resonance imaging deserve further investigation. Lastly, the prognostic values of most biomarkers in COVID‐19 are derived from retrospective analyses. Prospective studies are required to validate these markers for guiding clinical decision‐making and to facilitate their translation into clinical management pathways.

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“…MiR-15a-5p antagomiR denies the inflammatory pathway in both macrophages and septic mouse models via nuclear factor kappa B (NF-κB) signaling inhibition and targeting TNF-α induced protein 3 (NFAIP3)-interacting protein 2 (TNIP2) [ 35 ]. MiR-15a and miR-16 expression are improved in the blood of septic newborn subjects and inhibit the LPS-promoted inflammation [ 36 ], and miR-15b drives the onset and evolution of sepsis in animal models [ 37 ]. Research shows that miR-15b-5p expression predicts COVID-19 severity and it is involved in mammalian target of rapamycin (mTOR) signaling pathway in sepsis-induced acute kidney injury [ 37 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

“…MiR-15a and miR-16 expression are improved in the blood of septic newborn subjects and inhibit the LPS-promoted inflammation [ 36 ], and miR-15b drives the onset and evolution of sepsis in animal models [ 37 ]. Research shows that miR-15b-5p expression predicts COVID-19 severity and it is involved in mammalian target of rapamycin (mTOR) signaling pathway in sepsis-induced acute kidney injury [ 37 , 38 ]. However, the mechanistic role of miR-15b in septic EC has not yet been clearly explained.…”

Section: Introductionmentioning

confidence: 99%

MiR-15b-5p and PCSK9 inhibition reduces lipopolysaccharide-induced endothelial dysfunction by targeting SIRT4

et al. 2023

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Background Endothelial dysfunction and deregulated microRNAs (miRNAs) participate in the development of sepsis and are associated with septic organ failure and death. Here, we explored the role of miR-15b-5p on inflammatory pathways in lipopolysaccharide (LPS)-treated human endothelial cells, HUVEC and TeloHAEC. Methods The miR-15b-5p levels were evaluated in LPS-stimulated HUVEC and TeloHAEC cells by quantitative real-time PCR (qRT–PCR). Functional experiments using cell counting kit-8 (CCK-8), transfection with antagomir, and enzyme-linked immunosorbent assays (ELISA) were conducted, along with investigation of pyroptosis, apoptosis, autophagy, and mitochondrial reactive oxygen species (ROS) by cytofluorometric analysis and verified by fluorescence microscopy. Sirtuin 4 (SIRT4) levels were detected by ELISA and immunoblotting, while proprotein convertase subtilisin-kexin type 9 (PCSK9) expression was determined by flow cytometry (FACS) and immunofluorescence analyses. Dual-luciferase reporter evaluation was performed to confirm the miR-15b-5p–SIRT4 interaction. Results The results showed a correlation among miR-15b-5p, PCSK9, and SIRT4 levels in septic HUVEC and TeloHAEC. Inhibition of miR-15b-5p upregulated SIRT4 content, alleviated sepsis-related inflammatory pathways, attenuated mitochondrial stress, and prevented apoptosis, pyroptosis, and autophagic mechanisms. Finally, a PCSK9 inhibitor (i-PCSK9) was used to analyze the involvement of PCSK9 in septic endothelial injury. i-PCSK9 treatment increased SIRT4 protein levels, opposed the septic inflammatory cascade leading to pyroptosis and autophagy, and strengthened the protective role of miR-15b-5p inhibition. Increased luciferase signal validated the miR-15b-5p–SIRT4 binding. Conclusions Our in vitro findings suggested the miR-15b-5p–SIRT4 axis as a suitable target for LPS-induced inflammatory pathways occurring in sepsis, and provide additional knowledge on the beneficial effect of i-PCSK9 in preventing vascular damage by targeting SIRT4. Graphical Abstract

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Evaluation of altered miRNA expression pattern to predict COVID-19 severity

Cited by 12 publications

References 108 publications

MicroRNA-374b regulates SARS-CoV-2 viral protein mediated endothelial to mesenchymal transition by targeting c-FLIP

MicroRNA-374b regulates SARS-CoV-2 viral protein mediated endothelial to mesenchymal transition by targeting c-FLIP

Effective prognostic and clinical risk stratification in COVID‐19 using multimodality biomarkers

MiR-15b-5p and PCSK9 inhibition reduces lipopolysaccharide-induced endothelial dysfunction by targeting SIRT4

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