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Role of Non-Coding Rna in Cardiovascular Diseases

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Review Article | DOI: https://doi.org/10.31579/2639-4162/276

Role of Non-Coding Rna in Cardiovascular Diseases

  • Bon L.I *
  • Maksimovich N.Ye
  • M.F Shafa, A.L Shiraza

Grodno State Medical University, 80, Gorkogo St., 230009, Grodno, Republic of Belarus.

*Corresponding Author: Elizaveta I Bon, Candidate of biological science, Assistant professor of pathophysiology department named D. A. Maslakov, Grodno State Medical University; Grodno State Medical University, 80 Gorky St,230009, Grodno, Belarus.

Citation: Bon L. I, Maksimovich N.Ye, M.F Shafa, A.L Shiraza, (2025), Role of Non-Coding Rna in Cardiovascular Diseases, J. General Medicine and Clinical Practice, 8(7); DOI:10.31579/2639-4162/276

Copyright: © 2025, Elizaveta I Bon. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Received: 20 May 2025 | Accepted: 17 June 2025 | Published: 02 July 2025

Keywords: miRNA; lncRNA; cardiovascular diseases; myocardial infarction; cardiac hypertrophy; heart failure; atherosclerosis; arrhythmia; regeneration; apoptosis; drug delivery; therapeutic targets; RNA-based therapy

Abstract

Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are crucial regulators of gene expression and cellular function, with significant implications for cardiovascular diseases (CVDs) [1, 5]. These molecules influence a wide range of processes, including heart development, cardiomyocyte differentiation, cardiac remodeling, and vascular homeostasis. This review provides a detailed summary of their roles in these processes, highlighting their potential as diagnostic and therapeutic targets for CVDs. Understanding the mechanisms through which ncRNAs operate offers the possibility of innovative therapeutic strategies and underscores their importance in cardiovascular research.

Introduction

Cardiovascular diseases (CVDs) remain a leading global health challenge, contributing significantly to morbidity and mortality worldwide [11, 13, 14, 77, 78]. Despite advances in medical treatments and interventions, the complex molecular mechanisms underlying CVDs are not fully understood. Non-coding RNAs (ncRNAs) have emerged as key regulators in cardiovascular biology, offering new insights into disease pathogenesis and potential therapeutic interventions [5, 10, 73].  The exploration of ncRNAs represents a promising frontier in cardiovascular research, as they provide a deeper understanding of the molecular pathways involved in CVDs. Their ability to fine-tune gene expression makes them ideal candidates for therapeutic targeting. As we delve into the roles of ncRNAs, it becomes evident that they are not merely passive participants but active modulators of cardiovascular processes, which can be harnessed for therapeutic benefit.

MicroRNAs in Cardiovascular Biology:

MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules, typically 22 nucleotides in length, that negatively regulate gene expression at the post-transcriptional level [1, 59]. They bind to complementary sequences in the 3'-untranslated region (3'-UTR) of messenger RNAs (mRNAs), leading to mRNA degradation or translational repression [1, 59].  MiRNAs participate in various cellular processes within the cardiovascular system, including cardiomyocyte growth, contractility, angiogenesis, and the development and maintenance of cardiac rhythm [1, 2, 3, 4, 5]. These processes are critical for normal heart function and adaptability to various stressors. Altered miRNA expression profiles have been observed in the blood of patients with various CVDs, making them attractive candidates for non-invasive biomarkers for disease diagnosis and prognosis [1, 6, 7, 43, 44].  Specific miRNAs, such as miR-1, miR-133, and miR-195, have been shown to play critical roles in heart development and disease [1]. For instance, miR-1 is essential for cardiomyocyte proliferation, while miR-133 is involved in maintaining cardiac rhythm. Furthermore, the identification of circulating miRNAs as biomarkers has the potential to revolutionize early detection and monitoring of cardiovascular conditions, enabling clinicians to tailor interventions more effectively.

Long non-coding RNAs in Cardiovascular Disease:

Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that do not code for proteins but play significant roles in CVDs [5, 6, 7]. These molecules regulate gene expression and cellular signaling through diverse mechanisms, including chromatin remodeling, transcriptional regulation, and post-transcriptional processing [5, 8, 41, 42].  lncRNAs can function as signals, decoys, guides, and scaffolds, influencing mRNA stability, translation, and protein localization [5, 55, 56]. This multifunctionality allows lncRNAs to integrate various signaling pathways and cellular contexts. They also participate in sponging miRNAs, thus regulating miRNA activity and target gene expression [5, 50].  Specific lncRNAs, such as MALAT1, MIAT, and HOTAIR, have been implicated in various CVDs, including myocardial infarction, heart failure, and atherosclerosis [5, 118, 119, 117]. For example, MALAT1 has been shown to regulate cell proliferation and apoptosis in cardiomyocytes, impacting the overall health of cardiac tissue. The versatility of lncRNAs in regulating gene expression underscores their importance in maintaining cardiovascular homeostasis and their potential as therapeutic targets.

ncRNAs in Heart Development and Regeneration:

Both miRNAs and lncRNAs are essential for cardiac development and regeneration [1, 124, 50, 52]. Specific miRNAs, such as miR-199 and miR-590, have been shown to promote cardiomyocyte proliferation and heart regeneration after injury [1, 23, 47]. These findings highlight the regenerative potential of miRNAs, particularly in the context of myocardial infarction, where timely cellular proliferation is crucial for restoring heart function. lncRNAs, such as Braveheart (Bvht), play critical roles in cardiac lineage commitment and mesoderm isolation by interacting with chromatin-modifying complexes [66]. This indicates that lncRNAs are not only involved in adult cardiac physiology but also play foundational roles in embryonic development. Manipulating ncRNA expression shows therapeutic potential for promoting cardiac repair and rejuvenation after myocardial infarction [1, 50, 52, 53, 54]. 

For instance, overexpression of specific miRNAs or delivery of lncRNA-targeting molecules can enhance cardiomyocyte survival, promote angiogenesis, and reduce fibrosis in the infarcted heart. This regenerative capability highlights the importance of ncRNAs as potential therapeutic agents in cardiovascular medicine, offering hope for innovative treatments that harness the body’s innate healing processes.

ncRNAs in CVD Pathophysiology:

ncRNAs are intertwined in various cardiovascular conditions, including myocardial infarction (MI), heart failure (HF), cardiac hypertrophy, arrhythmias, and atherosclerosis [5, 101, 113, 115, 116, 117, 118, 119, 120, 121, 122, 123].

  • Myocardial Infarction (MI): In the context of MI, specific lncRNAs, such as CAIF, can inhibit autophagy and attenuate MI by blocking p53-mediated myocardin transcription [101]. The miR-15 family supports cardiomyocyte survival post-MI [1, 34]. Downregulation of miR-29 after MI results in scar formation due to increased collagen and extracellular matrix protein expression. These findings suggest that targeting these ncRNAs could improve outcomes in MI patients by enhancing the heart's ability to heal.
  • Heart Failure (HF): Dysregulation of miRNAs, such as miR-765 and miR-25, contributes to HF by disrupting calcium handling and promoting inflammation [1, 35]. lncRNAs, including OIP5-AS1, have been shown to exacerbate HF in a sex-specific manner [104]. Increased expression of miR-30d has been shown to protect cardiomyocytes from inflammation and cell death in the context of heart failure, indicating potential therapeutic strategies involving miR-30d modulation. Understanding these pathways could lead to targeted therapies that mitigate HF progression and improve patient quality of life.
  • Cardiac Hypertrophy: lncRNAs, such as Ahit and Chast, have been implicated in the pathogenesis of cardiac hypertrophy by modulating signaling pathways and gene expression [113, 78]. The lncRNA CHRF regulates cardiac hypertrophy by targeting miR-489 [115]. Insights into these regulatory mechanisms open avenues for targeting lncRNAs in the treatment of hypertrophic cardiomyopathy, potentially halting or reversing pathological remodeling of the heart.
  • Arrhythmias: miRNAs, such as miR-1 and miR-133, play an important role in the pathophysiology of arrhythmias by affecting cardiac conduction and electrical activity [31, 32]. Their precise regulation is crucial for maintaining normal cardiac rhythm and preventing arrhythmic events. Abnormal expression of these miRNAs can lead to disrupted electrical signaling, increasing the risk of life-threatening arrhythmias.
  • Atherosclerosis: In atherosclerosis, miRNAs regulate endothelial and smooth muscle cell function, influencing inflammation, lipid metabolism, and remodeling [1, 13, 46, 45, 4, 34]. lncRNAs can also modulate macrophage activation and cholesterol homeostasis in atherosclerotic plaques. For example, miR-33a and miR-122 have been described as regulators of lipid homeostasis [40, 41], illustrating the pivotal role of ncRNAs in lipid metabolism and atherosclerotic progression. Targeting these ncRNAs could provide new strategies for managing atherosclerosis and its complications.

Therapeutic Strategies Targeting ncRNAs in CVDs:

Emerging therapeutic strategies targeting ncRNAs in CVDs include:

  • miRNA Mimics: Small, chemically synthesized double-stranded RNAs that imitate endogenous miRNAs and induce gene silencing [1]. These mimics can restore normal miRNA function in cases where endogenous levels are reduced, potentially reversing disease processes.
  • AntagomiRs: Synthetic RNA molecules designed to silence aberrantly expressed miRNAs by binding to them and inhibiting their actions [1]. This approach can potentially reverse pathological conditions associated with dysregulated miRNA expression, offering a targeted method to address specific CVDs.
  • miRNA Sponges: Transcripts containing multiple complementary regions for miRNAs, resulting in their sequestration and reduced activity [1]. By sponging specific miRNAs, these constructs can modulate gene expression and impact disease outcomes, providing a novel mechanism for therapeutic intervention.
  • siRNAs and ASOs: Short interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) are utilized to target and degrade specific lncRNAs [60, 61]. These strategies allow for precise modulation of lncRNA expression, which could be crucial for therapeutic interventions aimed at correcting gene expression dysregulation.

Delivery Systems:

Innovative delivery systems, such as lentiviral vectors, liposomes, and exosomes, are being explored to enhance the efficacy and specificity of ncRNA-based therapies [69, 70, 71, 72, 73]. Effective delivery mechanisms are essential to ensure that therapeutic ncRNAs reach their targets in the cardiovascular system while minimizing off-target effects. Advances in nanotechnology and biomaterials are paving the way for more efficient delivery systems that can improve the bioavailability and stability of ncRNA therapeutics.

Limitations and Future Directions:

Despite advances, challenges remain in translating ncRNA-based therapies to the clinic, including species-specific differences, off-target effects, immunogenicity, and drug delivery [5, 98, 99, 100]. Further research is needed to fully harness the therapeutic potential of ncRNAs and develop safe and effective treatments for CVDs [5, 91, 92, 93, 94, 95, 96, 97].

Future Research Directions:

Future research should focus on:

  • Identifying novel ncRNAs involved in CVD pathogenesis, which could lead to new biomarkers and therapeutic targets. The discovery of previously uncharacterized ncRNAs may unlock new avenues for treatment.
  • Elucidating the precise mechanisms of ncRNA action in different cardiovascular cell types, enhancing our understanding of their roles in health and disease. This knowledge could facilitate the development of cell-type-specific therapies.
  • Developing more specific and efficient delivery systems for ncRNA-based therapeutics, which is critical for improving clinical outcomes. Innovations in delivery methods could enhance therapeutic efficacy while reducing side effects. 
  • Conducting clinical trials to evaluate the safety and efficacy of ncRNA-based therapies for CVDs, paving the way for their integration into standard medical practice. These trials are essential for establishing the clinical relevance of ncRNA-based interventions.

Conclusion:

Non-coding RNAs are crucial regulators in cardiovascular biology and offer potential therapeutic avenues for treating CVDs [1, 64, 76, 99]. A deeper understanding of their mechanisms and improved delivery strategies are essential for realizing their clinical potential [5, 83, 84, 85, 86, 87, 88, 89, 90]. The development of ncRNA-based therapies holds great promise for improving the treatment and prevention of CVDs. By advancing our knowledge of these regulatory molecules, we can unlock new strategies for combating cardiovascular diseases and improving patient outcomes. The future of cardiovascular medicine may well hinge on our ability to manipulate these powerful regulators of gene expression.

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