Thailand Medical News Exclusive: Deciphering the Intricate Role Of MiRNAs In Heart Disorders In COVID-19

Thailand Medical News Exclusive: Over the past 15 years, small non-coding RNAs, particularly microRNAs (miRNAs), have garnered significant attention for their potential role in gene expression regulation and disease diagnosis. Their role in the COVID-19 disease caused by the SARS-CoV-2 is gradually being unveiled by a small group of researchers globally who have the relevant expertise in this new branch of medical sciences.



(Please note that this series of exclusive research and articles have been created to correlate with the release of our range of new phyto based prophylactics and therapeutics for specific COVID-19 and Long COVID related issues that target specific cellular pathways, tissues and organs ie heart, brain, liver, kidney, vascular, immune involvements etc.)
 
Introduction to MiRNAs
MiRNAs, a class of endogenous non-coding RNAs, are encoded by both viral genomes and the human host cell, contributing to viral replication promotion or host defense evasion.
 
These molecular entities are involved in a spectrum of cellular functions, including immune regulation, proliferation, autophagy, and more. The complex landscape of miRNA activities extends to antiviral immune responses, influencing the severity of respiratory disorders, diabetes, heart conditions, and renal failure in the context of COVID-19.
 
Moreover, miRNAs play pivotal roles in host antiviral defenses against various viruses, spanning herpes virus, polyomavirus, retroviruses, pestivirus, hepacivirus, and SARS-CoV-2.
 
Their influence is far-reaching, affecting critical aspects of the angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) regulation, key receptors and co-receptors facilitating virus entry and fusion. For instance, miRNAs can modulate the expression of ACE2 and TMPRSS2, making them potential therapeutic targets in COVID-19 management.
 
However, the complex interplay between viral and host miRNAs and their precise effects on the cellular response to the virus remains a subject of ongoing investigation.
 
The diverse array of small RNAs, including miRNAs, encompasses various categories such as miRNA, siRNA, and PIWI-interacting RNA (piRNA), with miRNAs being the most extensively studied. These minute (~22 nucleotides) non-coding RNAs are central to the regulatory network of gene expression, impacting up to a third of human genes. The journey to miRNA identification has been accelerated by the advent of next-generation sequencing techniques and in silico methods, which have transformed the landscape of miRNA research. Publicly accessible databases like MiRBase, miRDB, VIRmiRNA, and Starbase have aided in cataloging and understanding miRNA functions. MiRNAs are named following a specific nomenclature, with mature miRNAs assigned a numeric identifier preceded by the prefix "miR." Differentiation between animal and plant miRNAs is achieved through the use of a dash symbol in animal miRNAs.
 
Furthermore, pre-miRNAs in animals are denoted in lowercase (e.g., mir-14), whereas plant pre-miRNAs are named differently. Cross-species identification employs a three-letter prefix denoting the species name, ensuring consistency across organisms.
 
MiRNA biogenesis is a tightly controlled process occurring in two main stages, guided by ribonuclease III proteins (R Nase III). The canonical pathway involves processing by Drosha and Dicer, with Drosha cleaving primary miRNA (pri-miRNA) transcripts to yield precursor miRNAs (pre-miRNAs), which are then transported to the cytoplasm. Subsequently, Dicer produces mature miRNAs by cleaving the pre-miRNAs, one strand of which is integrated into the RNA-induced silencing complex (RISC), facilitating gene silencing. Interestingly, non-canonical pathways, including miRtrons and tRNA-derived RNA fragments, have emerged, providing an additional layer of complexity to miRNA biogenesis. These pathways allow for the generation of miRNAs with distinct functions, shedding light on their diverse roles in various physiological and pathological processes.
 
MiRNAs, acting as post-transcriptional regulators, influence gene expression through interactions with mRNA sequences, primarily within the 3'-untranslated region (3'-UTR). Their control over gene expression is dynamic, modulating cellular processes until reaching a stable state. The intricate regulatory dance is orchestrated by the miRNA-induced silencing complex (miRISC), consisting of AGO proteins and GW182 proteins, which are involved in mRNA deadenylation, translation inhibition, and degradation. Non-canonical interactions further contribute to miRNA-mediated gene regulation, expanding the scope of their influence.
 
In the context of COVID-19, the intricate connection between SARS-CoV-2 infection and cardiovascular diseases is now evident, with severe COVID-19 cases presenting a range of cardiovascular complications.
 
MicroRNAs (miRNAs) - Unveiling the Complex Connection between Heart Disorders.
 
The intricate interplay between cardiovascular diseases (CVD) and the novel coronavirus, SARS-CoV-2, has emerged as a significant area of investigation, with COVID-19 patients often exhibiting severe cardiovascular complications.
 
The impact of SARS-CoV-2 infection on the arterial system becomes evident during the acute phases of the disease, triggering a series of events that include endothelial cell (EC) activation, vascular endothelitis, increased vascular permeability, and the formation of blood clots in severe cases.
 
The root cause of these cardiovascular disruptions lies in the widespread presence of viral receptors such as ACE2 and acetylated sialic acid residues on the surface of vascular ECs. While direct infection and replication of the virus within ECs is limited, the immune response cascade subsequently sets in motion processes that contribute to endothelial dysfunction.
 
Consequently, severe COVID-19 cases can manifest as a spectrum of cardiovascular issues, ranging from venous and arterial thrombosis to arrhythmias and myocardial infarctions.
 
Moreover, the intricate relationship between insulin resistance and adaptive cellular stress has been noted as a contributor to cardiovascular complications in severe COVID-19 cases.
 
Cardiomyocytes affected by SARS-CoV-2 infection exhibit cytotoxic effects that disrupt gene expression related to cellular metabolism and immune responses.
 
The pro-inflammatory cytokines released in response to the infection play a pivotal role in causing cardiac arrhythmias, hypotension, impaired blood flow, coagulation dysfunction, and microvascular clot formation, culminating in the obstruction of small arteries.
 
Emerging research and past Medical News reports have unveiled the involvement of several miRNAs in cardiovascular and metabolic anomalies, thereby influencing the disease trajectory and outcomes of critically ill patients. Notably, miRNAs such as miR-26b-5p and miR-200c-3p, which target ACE2 expression in the context of COVID-19, hold the potential to influence the severity of CVD.
 
The intricate regulatory interactions between miRNAs and ACE2 has come into the spotlight, shedding light on how these small RNA molecules can impact cardiovascular health.
 
MiR-200c, for instance, acts to suppress ACE2 expression in cardiomyocytes by targeting the 3'-UTR region of its mRNA, thereby inversely modulating ACE2 mRNA and protein expression.
 
Similarly, miR-98-5p has been shown to inhibit TMPRSS2 expression through binding to its 3'-UTR in human endothelial cells, offering another layer of miRNA-mediated regulation.
 
Intriguingly, bioinformatics studies have unveiled that miRNAs such as let-7e/miR-125a and miR-141/miR-200 play a role in modulating ACE2 and TMPRSS2 expression through 3'-UTR interactions, with their downregulation resulting in decreased receptor expression. The orchestration of these miRNAs becomes pivotal for the proper functioning of ACE2 and TMPRSS2 receptors. Additionally, miR-98 emerges as a key player in the regulation of TMPRSS2 in the context of COVID-19.
 
Further adding to the complexity, specific miRNAs have been implicated in the modulation of pro-inflammatory cytokine release within the heart. MiRNAs like miR-21-5p, miR-155-5p, and miR-214 have been linked to this process, while miR-125b and miR-223-3p are associated with the insulin signaling pathway and heart function. This dual role positions these miRNAs as crucial modulators that mitigate endothelial cell damage caused by excessive glucose levels and inflammation.
 
Notably, disruptions in the modulation of miR-590-3p, which serves as a regulator of IL-6 and TNF-α production, have been implicated in myocarditis and heart failure, underlining its significance in heart function regulation.
 
Adding to the intricate web of miRNA-mediated regulation, miR-146a emerges as a key player in reducing inflammation and cardiac injury through negative regulation of the NF-κB pathway. Its potential as a modulator gains further significance in COVID-19, where its expression reduction could potentially mitigate sepsis-induced cardiac failure or diabetes mellitus. MiR-30e-3p, a miRNA implicated in cardiovascular complications due to SARS-CoV-2, plays a role in suppressing virus replication by binding to complementary regions within the viral genome.
 
Past studies have uncovered a significant correlation between circulating miR-133a levels and individuals with cardiopulmonary disorders. Interestingly, these studies demonstrated an inverse relationship between miR-133a expression and neutrophil counts, suggesting a potential link between neutrophil activation and miRNA expression. This finding further ties into the cardiovascular context, where neutrophil degranulation and extravasation can contribute to myocyte damage and subsequent release of miR-133a.
 
Intriguingly, certain miRNAs have been found to be significantly upregulated in cardiovascular disorders, potentially offering novel avenues for intervention. MiR-423-5p, miR-23a-3p, and miR-195-5p are among the miRNAs that exhibit dramatic enhancement in cardiovascular anomalies. Interestingly, their reduced expression could potentially lead to decreased susceptibility to severe COVID-19 infection in individuals with pre-existing CVD. Conversely, miR-153, miR-208a-3p, and miR-375 have shown a positive correlation with heart disorders and myocardial damage, emphasizing their potential as therapeutic targets for heart disease treatment.
 
Notably, miR-208a and miR-375, highly expressed in dilated cardiomyopathy patients, have been implicated in promoting apoptosis in ischemic cardiomyocytes, and their modulation presents a promising avenue for improving heart disease outcomes.

In conclusion, the emerging understanding of the role of miRNAs in the intricate web of cardiovascular complications associated with severe COVID-19 infection opens up exciting possibilities for targeted therapeutic interventions.
 
Manipulation of specific miRNAs and the development of anti-miRNA therapies could potentially alleviate symptoms and improve cardiac function in individuals grappling with the challenges posed by severe COVID-19.
 
As the research continues to unveil the nuances of miRNA-mediated regulation in the context of COVID-19 and cardiovascular disorders, new avenues for personalized medicine and innovative interventions may pave the way towards better patient outcomes and improved public health.
 
We will be continuing this exclusive series of article on the role of MiRNAs on various as aspects of the COVID-19 diseases and also in Long COVID.
 
List Of Key References:
 
Role of microRNAs in COVID-19 with implications for therapeutics
https://pubmed.ncbi.nlm.nih.gov/34601190/
 
Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19)
https://pubmed.ncbi.nlm.nih.gov/32219357/
 
Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target
 
COVID-19 and the cardiovascular system
https://pubmed.ncbi.nlm.nih.gov/32139904/
 
Cardiovascular signatures of COVID-19 predict mortality and identify barrier stabilizing therapies
https://pubmed.ncbi.nlm.nih.gov/35405523/
 
MicroRNAs targeting the SARS-CoV-2 entry receptor ACE2 in cardiomyocytes
https://pubmed.ncbi.nlm.nih.gov/32891636/
 
miR-200c is upregulated by oxidative stress and induces endothelial cell apoptosis and senescence via ZEB1 inhibition
https://pubmed.ncbi.nlm.nih.gov/21527937/
 
ACE2 interaction networks in COVID-19: a physiological framework for prediction of outcome in patients with cardiovascular risk factors
https://pubmed.ncbi.nlm.nih.gov/33233425/
 
miR-98 regulates TMPRSS2 expression in human endothelial cells: key implications for COVID-19
https://pubmed.ncbi.nlm.nih.gov/33143053/
 
Integrative analysis of miRNA and mRNA sequencing data reveals potential regulatory mechanisms of ACE2 and TMPRSS2
https://pubmed.ncbi.nlm.nih.gov/32726325/
 
Engulfment of apoptotic cells by macrophages: a role of microRNA-21 in the resolution of wound inflammation
https://pubmed.ncbi.nlm.nih.gov/24391209/
 
The role of IgG Fc receptors in antibody-dependent enhancement
https://pubmed.ncbi.nlm.nih.gov/32782358/
 
miR-223-3p reduces high glucose and high fat-induced endothelial cell injury in diabetic mice by regulating NLRP3 expression
https://pubmed.ncbi.nlm.nih.gov/32765674/
 
Dysregulated CD4+ T cells and microRNAs in myocarditis
https://pubmed.ncbi.nlm.nih.gov/32269577/
 
COVID-19 virulence in aged patients might be impacted by the host cellular microRNAs abundance/profile
https://pubmed.ncbi.nlm.nih.gov/32489698/
 
Levels of circulating miR-133a are elevated in sepsis and predict mortality in critically ill patients
https://pubmed.ncbi.nlm.nih.gov/24413579/
 
Myeloperoxidase and C-reactive protein have combined utility for long-term prediction of cardiovascular mortality after coronary angiography
https://pubmed.ncbi.nlm.nih.gov/20223364/
 
Role of the endothelial surface layer in neutrophil recruitment
https://pubmed.ncbi.nlm.nih.gov/25979432/
 
The role of microRNAs in myocardial infarction: from molecular mechanism to clinical application
https://pubmed.ncbi.nlm.nih.gov/28362341/
 
Therapeutic inhibition of miR-375 attenuates post-myocardial infarction inflammatory response and left ventricular dysfunction via PDK-1-AKT signalling axis
https://pubmed.ncbi.nlm.nih.gov/28371849/
 
MicroRNAs and SARS-CoV-2 life cycle, pathogenesis, and mutations: biomarkers or therapeutic agents
https://pubmed.ncbi.nlm.nih.gov/33382348/
 
Human MicroRNAs interacting with SARS-CoV-2 RNA sequences: computational analysis and experimental target validation
https://pubmed.ncbi.nlm.nih.gov/34163530/
 
What is the potential function of microRNAs as biomarkers and therapeutic targets in COVID-19
https://pubmed.ncbi.nlm.nih.gov/32526370/
 
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