MicroRNA Targets in Cardiovascular Pharmacology

Abstract

MicroRNAs -- small non-coding RNA molecules of 18-25 nucleotides that post-transcriptionally regulate gene expression by binding to complementary sequences in the 3'-untranslated region of target mRNAs, inducing translational repression or mRNA degradation -- have emerged as a new class of cardiovascular drug targets and circulating biomarkers with transformative potential for precision cardiovascular medicine. Individual microRNAs regulate the expression of multiple target genes simultaneously, enabling single microRNA inhibition or mimicry to modulate entire pathological gene networks -- a pharmacological efficiency not achievable with conventional single-target small molecules. The cardiovascular system is particularly dependent on miRNA-mediated gene regulation: miR-208a controls the cardiac myosin heavy chain isoform switch that occurs in pathological cardiac hypertrophy; miR-21 mediates cardiac fibrosis through PTEN-Akt and Spry1 pathway regulation; and the miR-17-92 cluster governs cardiac progenitor cell proliferation and coronary angiogenesis. This comprehensive review systematically evaluates 247 miRNA-cardiovascular target relationships from 84 published studies, classifying them across six cardiovascular pathological domains -- cardiac hypertrophy, heart failure, myocardial infarction/ischaemia-reperfusion, cardiac fibrosis, arrhythmia, and atherosclerosis-- and assessing their pharmacological tractability as drug targets. A miRNA Cardiovascular Target Score (mCTS) integrating target validation strength, therapeutic window, delivery feasibility, and clinical biomarker utility is developed and validated. miR-208a inhibition (cardiac hypertrophy; mCTS 0.87) and miR-21 inhibition (cardiac fibrosis; mCTS 0.84) are identified as the highest-priority therapeutic targets, with miravirsen (anti-miR-122; hepatitis C) establishing the clinical precedent for anti-miR therapy as a validated pharmacological modality.