Immune microRNAs drive new frontiers in cardiovascular disease research

Cardiovascular diseases (CVDs) continue to dominate global mortality statistics, with immune dysregulation emerging as a central feature in their pathogenesis. This review by Gareev et al. focuses on immune-derived microRNAs (immuno-miRs) as pivotal modulators of immune responses in cardiovascular settings, highlighting their roles in pathophysiology, diagnostic potential, and therapeutic promise.

Introduction

The authors introduce CVDs as a global health crisis, exacerbated by the interplay between immune dysregulation and cardiovascular remodeling. Immune cells like macrophages and T cells, while crucial for homeostasis, can trigger chronic inflammation, fibrosis, and plaque instability when misregulated. Recent discoveries spotlight miRNAs, small non-coding RNAs secreted by immune cells, as key players in controlling these immune responses through gene silencing.

miRNAs in immune cell development and function

Immuno-miRs regulate both innate and adaptive immune responses, influencing the development, activation, and function of various immune cells.

1. In innate immunity, miRNAs such as miR-223, miR-155, and miR-146a modulate macrophage polarization, neutrophil activation, and inflammatory signaling pathways like NF-κB.
2. In adaptive immunity, miRNAs like miR-181a, the miR-17-92 cluster, and miR-142-3p/5p orchestrate T and B cell responses, including Treg function, T cell activation thresholds, and humoral immunity.

Intercellular communication via extracellular vesicles

The review explores how immune cells secrete extracellular vesicles (EVs) loaded with miRNAs, enabling communication with cardiomyocytes, endothelial cells, and other immune cells. For example, miR-223-enriched EVs reduce endothelial inflammation, while miR-155-containing EVs amplify pathological responses. This mode of communication underscores miRNAs' potential as therapeutic targets and biomarkers.

miRNAs and cardiovascular risk factors

miRNAs modulate inflammation across major CVD risk factors:

1. Obesity: miRNAs such as miR-34a and miR-103 in epicardial adipose tissue regulate macrophage polarization and Th2 chemokines
2. Hypertension: miRNAs like miR-214 and miR-31 contribute to T cell–driven vascular inflammation.
3. Diabetes: Downregulation of miR-146a and upregulation of miR-21 drive macrophage activation and fibrosis.
4. Dyslipidemia and Atherosclerosis: miRNAs including miR-33, miR-92a, and miR-126 affect cholesterol metabolism, foam cell formation, and endothelial function.

The authors highlight how dysregulated miRNAs interconnect these risk factors, making them potential biomarkers for early detection and targets for prevention.

miRNA regulation of specific immune cells in CVDs

The review provides detailed mechanistic insights into how miRNAs regulate individual immune cell types in cardiovascular pathology:

Macrophages:

miR-21 promotes M2 polarization and tissue repair.

miR-155 supports M1 pro-inflammatory responses and plaque instability.

miR-223 restrains macrophage overactivation and reduces plaque burden.

Neutrophils:

miR-146a and miR-223 suppress excessive neutrophil activity, mitigating post-infarction injury.

T Lymphocytes:

miR-181a supports T cell activation; its decline contributes to immune senescence in aging.

The miR-17-92 cluster regulates effector/memory T cell function.

T Regulatory Cells (Tregs):

miRNAs such as miR-142, miR-155, and miR-4281 control FOXP3 expression and Treg stability.

miR-155 demonstrates dual roles, being pro-inflammatory in macrophages but essential for Treg proliferation and suppression.

CTLA-4 signaling and its miRNA regulation

The article explores the CTLA-4 immune checkpoint, crucial for tempering T cell activation. CTLA-4 is regulated by miRNAs including miR-155, miR-9, miR-105, and miR-487a-3p. Targeting these regulatory axes may enhance Treg function, reduce vascular inflammation, and improve outcomes post-myocardial infarction.

Clinical implications and therapeutic potential

The authors detail miRNA-based therapies, such as:

1. miRNA mimics (e.g., miR-21 delivery to enhance cardiac repair)
2. AntagomiRs (e.g., miR-155 inhibitors to suppress inflammation)

Circulating miRNAs, due to their stability and specificity, are emerging as non-invasive biomarkers for diagnosis and prognosis across CVD subtypes, including heart failure and atherosclerosis.

Future directions and limitations

Despite compelling preclinical data, several challenges remain:

1. Target specificity and delivery: Precise, tissue-specific delivery methods are needed.
2. Clinical variability: miRNA expression can vary by individual, disease stage, and environment.
3. Regulatory complexity: miRNAs often act in networks, requiring multiparametric therapeutic strategies.

Future research must refine miRNA delivery platforms, conduct larger clinical trials, and integrate miRNA profiling into personalized cardiovascular care.

Conclusion

Immuno-miRs represent a transformative opportunity in cardiovascular medicine. They serve as crucial regulators of immune responses, promising biomarkers, and emerging therapeutic targets. Harnessing their full potential could revolutionize the early diagnosis, risk assessment, and treatment of CVDs in a minimally invasive and precision-guided manner.