MICRORNA-MEDIATED REGULATION OF MACROPHAGE POLARIZATION IN CARDIOVASCULAR INFLAMMATION AND ATHEROSCLEROTIC DISEASE

Abstract

Atherosclerosis remains the leading cause of cardiovascular morbidity and mortality worldwide, driven by chronic inflammation and dysregulated lipid metabolism within arterial walls. Macrophages are central orchestrators of atherosclerotic plaque development, with their functional phenotype—ranging from pro-inflammatory M1 to anti-inflammatory M2 states—critically determining plaque stability and disease progression. MicroRNAs (miRNAs), small non-coding RNAs that post-transcriptionally regulate gene expression, have emerged as master regulators of macrophage polarization and function in atherosclerosis. This review synthesizes current evidence on miRNA-mediated control of macrophage phenotype switching, lipid handling, and inflammatory responses in cardiovascular disease. We examine key miRNAs that promote M1 polarization (miR-155, miR-146a, miR-21) and M2 polarization (miR-223, miR-125b, miR-181b), their validated molecular targets, and the signaling pathways they modulate, including NF-κB, TLR4, NLRP3 inflammasome, PI3K/AKT, and PPARγ/LXR axes. Special emphasis is placed on miRNA regulation of cholesterol transport via ABCA1/ABCG1 and foam cell formation. We evaluate the translational potential of miRNAs as circulating biomarkers for cardiovascular risk stratification and as therapeutic targets through antagomirs, mimics, and nanoparticle delivery systems. Despite promising preclinical data, significant challenges remain in delivery specificity, off-target effects, and clinical validation. This comprehensive review highlights the mechanistic complexity of miRNA networks in macrophage biology and identifies critical knowledge gaps that must be addressed to advance miRNA-based cardiovascular therapeutics from bench to bedside.