The role of circular RNA in cardiovascular diseases

Cardiology Updates: Cardiovascular diseases (CVDs) are the leading cause of death worldwide, posing significant challenges for medical professionals globally. A novel class of non-coding RNAs, known as circular RNAs (circRNAs), has emerged as a crucial player in understanding and potentially treating CVDs. Researchers from Tongji Hospital and Tongji Medical College, Huazhong University of Science and Technology, China, have conducted extensive studies on circRNAs, shedding light on their biogenesis, function, and potential clinical applications.


The role of circular RNA in cardiovascular diseases

Understanding Circular RNA
CircRNAs are unique in their structure, forming covalently closed loop molecules without free ends. This structure grants them remarkable stability, making them resistant to degradation by enzymes that typically break down linear RNAs. Discovered initially in the 1970s, circRNAs were once thought to result from splicing errors. However, advances in sequencing technologies have revealed their prevalence in mammalian tissues, including those of humans, mice, and monkeys. This Cardiology Updates news report will explore their role in CVDs.

Characteristics and Types of CircRNAs
CircRNAs are classified into three types based on their sequence composition: exon type (EcircRNA), intron type (ciRNA), and exon–intron type (EIciRNA). EcircRNAs, which are highly expressed, are typically composed of exons from coding genes and are predominantly located in the cytoplasm. In contrast, ciRNAs are more abundant in the nucleus and play a significant role in gene regulation.
 
Biogenesis of CircRNAs
CircRNAs are produced during the RNA splicing process and can be regulated by various mechanisms, including flanking inverted-repeat sequences, RNA-binding proteins (RBPs), lasso structures, and m6A modification.
 
-Flanking Inverted-Repeat Sequences: Short interspersed elements (SINEs) and long interspersed elements (LINEs), especially Alu elements, facilitate the formation of circRNAs by bringing the ends of pre-mRNA closer together.
 
-RBPs: Proteins like DHX9 and ADAR1 can inhibit circRNA formation, while others like QKI and FUS promote it by binding to specific sequences.
 
-Lasso Structures: These structures, formed during RNA splicing, are essential for the production of ciRNAs.
 
-m6A Modification: This chemical modification can also regulate circRNA production by affecting RNA stability and splicing.
 
Functions of CircRNAs
CircRNAs play diverse roles in cellular processes, including acting as microRNA (miRNA) sponges, binding to proteins, translating proteins, modulating mRNA translation, and regulating gene transcription.
 
-miRNA Sponges: CircRNAs can bind to miRNAs, preventing them from suppressing their target genes. For example, ciRS-7 binds to miR-7, influencing central nervous system regulation.
 
-Binding Proteins: CircRNAs can interact with proteins, altering their function and stability. CircACC1 binds to AMPK subunits, maintaining energy homeostasis in cells.
 
-Translating Proteins: Certain circRNAs can be translated into proteins via internal ribosome entry sites (IRES) or m6A modifications, which can impact cellular functions and disease processes.
 
CircRNAs in Cardiovascular Diseases
CircRNAs are implicated in various CVDs, including atherosclerosis, arterial injury, aortic aneurysm or dissection, myocardial infarction (MI), hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), diabetic cardiomyopathy, and doxorubicin-induced cardiotoxicity.
 
Atherosclerosis
CircRNAs play a significant role in the development and progression of atherosclerosis. For instance, circANRIL, derived from a risk locus on chromosome 9p21.3, disrupts rRNA splicing and contributes to atherosclerosis. Other circRNAs, such as circ_0030042 and circRSF1, regulate endothelial cell function and inflammation, highlighting their potential as therapeutic targets.
 
Arterial Injury
CircRNAs are involved in the response to arterial injury, which often occurs after coronary interventions. CircSirt1, for example, inhibits vascular smooth muscle cell (VSMC) proliferation and neointima formation, reducing the risk of restenosis. CircMAP3K5 also plays a role in mitigating arterial injury by regulating TET2 expression.
 
Aortic Aneurysm or Dissection
Specific circRNAs are associated with aortic aneurysm and dissection. CircCdyl promotes M1 macrophage polarization and inflammation, exacerbating aneurysm formation. Identifying and targeting these circRNAs could provide new therapeutic avenues for these life-threatening conditions.
 
Myocardial Infarction (MI)
During MI, circRNAs such as circSNRK and circFEACR play crucial roles in cardiomyocyte apoptosis and regeneration. These circRNAs influence various signaling pathways, offering potential targets for therapeutic intervention to improve heart function post-MI.
 
Hypertrophic Cardiomyopathy
CircRNAs like circSlc8a1 and HRCR regulate cardiac hypertrophy and heart failure. These molecules modulate gene expression and protein interactions, providing insights into the mechanisms underlying hypertrophic cardiomyopathy and potential therapeutic targets.
 
Dilated Cardiomyopathy (DCM)
CircRNAs are involved in the pathogenesis of DCM, with studies identifying differentially expressed circRNAs in heart tissues from patients. These findings suggest that circRNAs could serve as biomarkers and therapeutic targets for DCM.
 
Diabetic Cardiomyopathy
CircRNAs such as DICAR and CACR are implicated in diabetic cardiomyopathy, affecting cardiomyocyte hypertrophy and apoptosis. Targeting these circRNAs could help manage this severe complication of diabetes.
 
Doxorubicin-Induced Cardiotoxicity
CircRNAs can mitigate the cardiotoxic effects of doxorubicin, a common chemotherapeutic drug. Circ-INSR and CircITCH, for example, protect cardiomyocytes from doxorubicin-induced damage, highlighting their potential as therapeutic agents.
 
Conclusion
In conclusion, circRNAs represent a promising frontier in cardiovascular research, offering new insights into the mechanisms of CVDs and potential therapeutic targets. Their unique properties, including stability and diverse functions, make them suitable as biomarkers and therapeutic agents. Understanding how circRNAs interact with other molecular pathways in cardiovascular diseases opens up new possibilities for diagnosis, treatment, and prevention. The discovery of specific circRNAs involved in various cardiovascular conditions highlights their importance in both basic research and clinical applications.
 
As researchers continue to unravel the complexities of circRNA biology, their findings will likely lead to the development of novel diagnostic tools and targeted therapies. For example, targeting circRNAs that regulate key pathways in atherosclerosis, myocardial infarction, or diabetic cardiomyopathy could offer more precise treatment options with fewer side effects compared to current therapies.
 
Moreover, the stability of circRNAs makes them excellent candidates for non-invasive biomarkers. Their presence in blood and other body fluids allows for the development of simple blood tests that could predict disease onset or progression, enabling early intervention and better patient outcomes.

The potential applications of circRNAs extend beyond cardiovascular diseases. As research progresses, circRNAs may become valuable tools in other medical fields, such as oncology, neurology, and infectious diseases. Their ability to regulate gene expression and interact with proteins and other RNAs positions them as versatile molecules in the broader landscape of medical research.
 
The study findings were published in the peer-reviewed journal: Biomolecules.
https://www.mdpi.com/2218-273X/14/8/952
 
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