MicroRNAs: An Apparent Switch for High-Altitude Pulmonary Edema

Alam, Perwez; Saini, Neeru; Pasha, M. A. Qadar

doi:10.2174/2211536604666151103121633

Cited by 15 publications

(18 citation statements)

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“…Recent published reports also shows that TGF-beta1 appear to be overproduced in COVID-19 patients [69]. Hsa-miR-9-5p, hsa-miR-98-5p and hsa-miR-23b-3p regulate TGFBR receptors during pulmonary disorders [68,70,71]. These miRNAs are part of the regulatory circuit identified in the present study and are antiviral host-miRNAs which can potentially target SARS-CoV-2 genes [10].…”

Section: Discussionsupporting

confidence: 71%

“…During HAPE, hypobaric hypoxia causes decrease in arterial oxygen leading to the pulmonary vasoconstriction and further leads to increase in pulmonary pressure. TGF-β signalling was identified to control pulmonary pressure in lungs and TGF-B1 and TGFBR receptors-1,2 complex are the major regulators of the signalling [68].Sustained increase in pulmonary pressure causes pulmonary hypertension, over perfusion that further leads to pulmonary vascular leakage causing edema. Recent published reports also shows that TGF-beta1 appear to be overproduced in COVID-19 patients [69].…”

Section: Discussionmentioning

confidence: 99%

“…Hence these miRNAs can be studied and their role in tissue necrosis in nSARS-CoV-2 infection can be explored. The literature also highlights commonality in pathophysiology like pulmonary pressure, lung fibrosis in both HAPE and SARS-CoV viral infection [53,68]. This factor is important in repurposing of drugs like Acetazolamide, Nifedipine and Phosphodiesterase inhibitors that have been proposed to be repurposed for COVID-19 [19].…”

Section: Discussionmentioning

confidence: 99%

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The miRNA-gene regulatory circuits in nSARS-CoV-2 and their potential correlations with pulmonary and thrombotic disorders

Khurana

Gupta

Sugadev

et al. 2020

Preprint

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In view of the worldwide spread of the novel Severe Acute Respiratory Syndrome Coronavirus 2 (nSARS-CoV-2) infection pandemic situation, research to repurpose drugs, identify novel drug targets, vaccine candidates, diagnostic markers etc have created a new race to curb the disease. To uncover nSARS-CoV-2-related important biological features and understanding the molecular basis of this disease, network biology and miRNA-gene regulatory motif-based approach is used. 11 antiviral human-microRNAs (miRNAs) which can potentially target SARS-CoV-2 genes were collated; their direct miRNA interactors were identified and a comprehensive nSARS-CoV-2 responsive miRNA:Transcription Factor (TF):gene coregulatory network was built. 1385 miRNA:TF:gene tripartite, Feed-Forward Loops (FFLs) were identified from the network. The network topology was mapped into the biological space and the overrepresented pathways were identified. Four regulatory circuits: hsa-mir-9-5p-EP300-PLCB4, hsa-mir-324-3p-MYC-HLA-F, hsa-mir-1827-E2F1-CTSV and hsa-mir-1277-5p-SP1-CANX are identified. These miRNA-gene regulatory circuits are found to regulate signalling pathways like virus endocytosis, viral replication, inflammatory response, pulmonary vascularization, cell cycle control, virus spike protein stabilization, antigen presentation, etc. Some novel computational evidences for understanding nSARS-CoV-2 molecular mechanisms controlled by these regulatory circuits is put forth. The novel associations of miRNAs and genes identified with this infection are open for experimental validation. Further, these regulatory circuits also suggest potential correlations/similarity in the molecular mechanisms during nSARS-CoV-2 infection and pulmonary diseases and thromboembolic disorders. A detailed molecular snapshot of TGF-β signalling pathway as the common mechanism that could play an important role in controlling common pathophysiology i.e. systemic inflammation, increased pulmonary pressure, ground glass opacities, D-dimer overexpression is also put forth.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The miRNA-gene regulatory circuits in nSARS-CoV-2 and their potential correlations with pulmonary and thrombotic disorders

Khurana

Gupta

Sugadev

et al. 2020

Preprint

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“…[27][28][29][30][31] In addition to genetic variation, epigenetics plays prominent role in HAPE and other diseases. [32][33][34][35] DNA methylation, acetylation, histone modifications/chromatin remodelling and post translational RNA regulations are…”

mentioning

confidence: 99%

Vascular homeostasis at high‐altitude: role of genetic variants and transcription factors

et al. 2020

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total number of manuscript pages -41 • total number of figures -4 • word count for the body of the text -7834 • type of contribution -review article AbstractHigh-altitude pulmonary edema (HAPE) occurs most frequently in non-acclimatized low landers on exposure to altitude ≥2500m. HAPE is a complex condition that involves perturbation of signaling pathways in vasoconstrictors, vasodilators, anti-diuretics and vascular growth factors. Genetic variations are instrumental in regulating these pathways and evidence is accumulating for a role of epigenetic modification in hypoxic responses. This review focuses on the crosstalk between HAPE-associated genetic variants and transcription factors, comparing high-altitude adapted and HAPE-afflicted subjects. This approach might ultimately yield biomarker information both to understand and to design therapies for high altitude adaptation.Evolution and physiological adaptation have permitted survival at the highest topographically elevated regions of the world. [1][2][3][4][5] Reduced air pressure at high-altitude decreases the partial pressure of inspired oxygen, affecting lungs, brain, heart and blood and can lead to a spectrum of high-altitude disorders including high-altitude pulmonary edema (HAPE), acute mountain sickness (AMS) and high-altitude cerebral edema (HACE). 6,7 This review focuses on HAPE. HAPE is a consequence of hypoxic pulmonary vasoconstriction leading to increased pulmonary arterial pressure and capillary stress failure. 8-11 HAPE victims have lower arterial oxygen saturation (SaO2) and higher heart rate, pulmonary vascular resistance and pulmonary vascular resistance index 12,13 than do unaffected sojourners to altitude. Clinically HAPE is characterized by dyspnoea, elevated body temperature, pink frothy sputum, tachypnoea, tachycardia, persistent cough and cyanosis. [14][15][16][17] Chest X-rays and CT scans show increased lung vascular markings and patchy shadows. 18,19 There have been great strides in understanding the clinical and physiological mechanisms of HAPE that has led to the discovery of successful treatments. Information on genetic contributions to this disorder has also grown rapidly over the last decade, partly to the development and implementation of newer genetic techniques. Candidate-gene approaches, advanced techniques such as Next-GenerationSequencing and Genome-Wide Association Studies have led to association of multiple genetic variants with high-altitude adaptation or maladaptation. [20][21][22][23][24][25][26] The majority of these genes belong to multiple, frequently related pathways. These include the renin-angiotensin aldosterone system, apelin signaling, nitric oxide signaling, and hypoxia induced signaling.These pathways regulate vasoactive molecules including angiotensin II, apelin, nitric oxide, aldosterone, and beta-adrenergics. [27][28][29][30][31] In addition to genetic variation, epigenetics plays prominent role in HAPE and other diseases. [32][33][34][35] DNA methylation, acetylation, histone modifications/chromatin rem...

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“…miRNAs are known to regulate a number of molecular mechanism during HA acclimatization or disorders, e.g. miR-16, -20b, -22 and -206 and 17/92 are downregulated during HAPE and are responsible for disruption of the ion channels and loss of cellular integrity (8). Increase in red blood cell count, haematocrit values and haemoglobin are established physiological response at HA.…”

Section: Introductionmentioning

confidence: 99%

HAHmiR.DB: A Server Platform For High Altitude Human miRNA-Gene Coregulatory Networks And Associated Regulatory-Circuits

Khurana

Gupta

Sugadev

et al. 2020

Preprint

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Rapid ascent to High Altitude (HA) can cause severe damage to body organs and may lead to many fatal disorders. During induction to HA, human body undergoes various physiological, biochemical, hematological and molecular changes to adapt to the extreme environmental conditions. Many literature references hint that gene-expression-regulation and regulatory molecules like microRNAs (miRNAs) and Transcription Factors (TFs) control adaptive responses during HA-stress. These biomolecules are known to interact in a complex combinatorial manner to fine-tune the gene expression and help in controlling the molecular responses during this stress and ultimately help in acclimatization. HAHmiR.DB (High-Altitude Human miRNA Database) is a unique, comprehensive, curated collection of miRNAs that have been experimentally validated to be associated with HA-stress; their level of expression in different altitudes, fold change, experiment duration, biomarker association, disease and drug association, tissue-specific expression level, Gene Ontology (GO) and Kyoto Encyclopaedia of Gene and Genomes (KEGG) pathway associations. As a server platform it also uniquely constructs and analyses interactive miRNA-TF-Gene coregulatory networks and extracts regulatory-circuits/Feed Forward Loops (FFLs) using in-house scripts. These regulatory circuits help to offer mechanistic insights in complex regulatory mechanisms during HA stress. The server can also build these regulatory networks between two and more miRNAs of the database and also identify the regulatory-circuits from this network. Hence HAHmiR.DB is the first-of its-kind database in HA research which a reliable platform to explore, compare, analyse and retrieve miRNAs associated with HA stress, their coregulatory networks and FFL regulatory circuits. HAHmiR.DB is freely accessible at http://www.hahmirdb.in

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MicroRNAs: An Apparent Switch for High-Altitude Pulmonary Edema

Cited by 15 publications

References 0 publications

The miRNA-gene regulatory circuits in nSARS-CoV-2 and their potential correlations with pulmonary and thrombotic disorders

The miRNA-gene regulatory circuits in nSARS-CoV-2 and their potential correlations with pulmonary and thrombotic disorders

Vascular homeostasis at high‐altitude: role of genetic variants and transcription factors

HAHmiR.DB: A Server Platform For High Altitude Human miRNA-Gene Coregulatory Networks And Associated Regulatory-Circuits

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