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Review
. 2024 Oct 16;25(10):368.
doi: 10.31083/j.rcm2510368. eCollection 2024 Oct.

Molecular Interplay in Cardiac Fibrosis: Exploring the Functions of RUNX2, BMP2, and Notch

Pavel Docshin  1 , Daniil Panshin  1 , Anna Malashicheva  1
Affiliations
Review

Molecular Interplay in Cardiac Fibrosis: Exploring the Functions of RUNX2, BMP2, and Notch

Pavel Docshin et al. Rev Cardiovasc Med. .

Abstract

Cardiac fibrosis, characterized by the excessive deposition of extracellular matrix proteins, significantly contributes to the morbidity and mortality associated with cardiovascular diseases. This article explores the complex interplay between Runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2), and Notch signaling pathways in the pathogenesis of cardiac fibrosis. Each of these pathways plays a crucial role in the regulation of cellular functions and interactions that underpin fibrotic processes in the heart. Through a detailed review of current research, we highlight how the crosstalk among RUNX2, BMP2, and Notch not only facilitates our understanding of the fibrotic mechanisms but also points to potential biomolecular targets for intervention. This article delves into the regulatory networks, identifies key molecular mediators, and discusses the implications of these signaling pathways in cardiac structural remodeling. By synthesizing findings from recent studies, we provide insights into the cellular and molecular mechanisms that could guide future research directions, aiming to uncover new therapeutic strategies to manage and treat cardiac fibrosis effectively.

Keywords: Notch signaling pathways; Runt-related transcription factor 2; bone morphogenetic protein 2; cardiac fibrosis; signaling interactions.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Visual summary of the role of Notch signaling in cardiac fibrosis. On the left, normal cardiac tissue is depicted with controlled fibroblast proliferation within the heart tissue, maintaining tissue integrity. In the center, the Notch signaling pathway acts as a critical regulator; upregulated Notch activity is shown to inhibit the secretion of pro-fibrotic markers such as transforming growth factor beta (TGFβ1), platelet derived growth factor B (PDGF-B), collagen 1 (COL1), and collagen 3 (COL3) by macrophages M1 and M2, thus reducing fibrosis. Notch signaling decreases fibroblast proliferation and promotes apoptosis, while inhibiting their differentiation into myofibroblasts, cells that contribute to pathological cardiac fibrosis, shown on the right. The pathological state is characterized by excessive deposition of extracellular matrix components, leading to impaired cardiac function. This figure was created with BioRender.com.
Fig. 2.
Fig. 2.
Schematic diagram of signaling pathways involved in cardiac fibrosis. It depicts two primary signaling cascades: the transforming growth factor beta (TGFβ) pathway on the left and the bone morphogenetic protein 2 (BMP2) pathway on the right, both converging on SMAD proteins (refers to homologies with C. elegans SMA (“small” worm phenotype) and Drosophila MAD (“mothers against decapentaplegic”) genes), which are critical mediators of fibrosis. In the TGFβ pathway, the receptor is shown activating SMAD2/3 complexed with Smad anchor for receptor activation (SARA). This complex subsequently activates Rho-associated kinase (ROCK), a downstream effector known to promote fibrosis, leading to the pathological remodeling of cardiac tissue, which is illustrated by a cluster of myocardial cells interlaced with fibrotic tissue. The BMP2 pathway involves SMAD6. Notably, SMAD6 forms a complex with Smurf1 (Smad ubiquitination regulatory factor 1), which negatively regulates the TGFβ pathway, providing a potential anti-fibrotic mechanism. Secreted protein acidic and rich in cysteine (SPARC)-related modular calcium binding 1 (SMOC1) is depicted as an inhibitor, shown by a downward red arrow, which suggests that it reduces the activity of SMADs or other intermediaries in the pathway, potentially leading to a decrease in fibrotic response. This figure was created with BioRender.com.
Fig. 3.
Fig. 3.
Visual summary of the role of Runt-related transcription factor 2 (RUNX2) in cardiac fibrotic processes. It depicts how a high-fat diet can lead to an increase in RUNX2 levels, which in turn results in a high deposition of the extracellular matrix in the aortic valve, symbolizing a profibrotic response. Additionally, the figure outlines the involvement of RUNX2 in myocardial cell repair, where it facilitates the proliferation of fibroblasts following MI. Notably, the diagram presents the dual nature of RUNX2: while its upregulation aids myeloid cell-induced fibroblast proliferation, its knockdown decreases the levels of key fibrotic markers such as alpha-1 type I collagen (COL1A1), alpha 1 chain of type III collagen (COL1A3), and transforming growth factor β1 (TGFβ1). This figure was created with BioRender.com.
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Grants and funding

This work was supported by Ministry of Science and HigherEducation of the Russian Federation (Agreement No. 075-15-2021-1075, dated 09/28/2021).

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