The Role of MicroRNAs in the Pathogenesis of Doxorubicin-Induced Vascular Remodeling

Abstract

Doxorubicin (DOX), a cornerstone chemotherapeutic agent, effectively combats various malignancies but is marred by significant cardiovascular toxicity, including endothelial damage, chronic heart failure, and vascular remodeling. These adverse effects, mediated by oxidative stress, mitochondrial dysfunction, inflammatory pathways, and dysregulated autophagy, underscore the need for precise therapeutic strategies. Emerging research highlights the critical role of microRNAs (miRNAs) in DOX-induced vascular remodeling and cardiotoxicity. miRNAs, such as miR-21, miR-22, miR-25, miR-126, miR-140-5p, miR-330-5p, miR-146, miR-143, miR-375, miR-125b, miR-451, miR-34a-5p, and miR-9, influence signaling pathways like TGF-β/Smad, AMPKa/SIRT, NF-κB, mTOR, VEGF, and PI3K/AKT/Nrf2, impacting vascular homeostasis, angiogenesis, and endothelial-to-mesenchymal transition. Despite existing studies, gaps remain in understanding the full spectrum of miRNAs involved and their downstream effects on vascular remodeling. This review synthesizes the current knowledge on miRNA dysregulation during DOX exposure, focusing on their dual roles in cardiovascular pathology and tumor progression. Strategies to reduce DOX cardiotoxicity include modulating miRNA expression to restore signaling balance, targeting pro-inflammatory and pro-fibrotic pathways, and leveraging miRNA inhibitors or mimics. This review aims to organize and integrate the existing knowledge on the role of miRNAs in vascular remodeling, particularly in the contexts of DOX treatment and the progression of various cardiovascular diseases, including their potential involvement in tumor growth.

Keywords: biomarker; doxorubicin; endothelium; heart disease; microRNA; tumor angiogenesis; vascular remodeling.

Figure 1

Alterations in the expressions of key known microRNAs during the development of specific cardiovascular pathologies (atherosclerosis, hypertension (arterial and pulmonary), and diabetic cardiovascular complications). ↑, overexpression; ↓, reduced expression.

Figure 2

Effects of doxorubicin on microRNA expression in modulating apoptosis, mitochondrial biogenesis, ferroptosis, pyroptosis, endoplasmic reticulum (ER) stress, and endothelial dysfunction. ↑, overexpression; ↓, reduced expression.

Figure 3

Key signaling pathways involved and their effects in vascular remodeling under doxorubicin exposure. ↑, activation; ↓, suppression; AKT, protein kinase B; AMPK, 5′ AMP-activated protein kinase; COX-2, cyclooxygenase-2; Cx43/Cx45, connexin 43/45; DOX, doxorubicin; ERK5, extracellular signal-regulated kinase 5; FOXO3a, forkhead box protein O3a; GSDMD, Gasdermin D; IL10, interleukin-10; JNK, c-Jun N-terminal kinases; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor erythroid 2-related factor 2; PI3K, phosphoinositide 3-kinases; ROS, reactive oxygen species; SIRT, silent information regulator 2 protein; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha; VEGFR, vascular endothelial growth factor receptor; ZO-1, zonula occludens-1.

Figure 4

The impact of doxorubicin on microRNA expression in vascular remodeling and tumor angiogenesis. ↑, activation; ↓, suppression.