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Review
. 2021 Jan;41(1):20-34.
doi: 10.1161/ATVBAHA.120.313791. Epub 2020 Oct 29.

Transcriptional Programming in Arteriosclerotic Disease: A Multifaceted Function of the Runx2 (Runt-Related Transcription Factor 2)

Yabing Chen  1   2 , Xinyang Zhao  3 , Hui Wu  4
Affiliations
Review

Transcriptional Programming in Arteriosclerotic Disease: A Multifaceted Function of the Runx2 (Runt-Related Transcription Factor 2)

Yabing Chen et al. Arterioscler Thromb Vasc Biol. 2021 Jan.

Abstract

Despite successful therapeutic strategies in the prevention and treatment of arteriosclerosis, the cardiovascular complications remain a major clinical and societal issue worldwide. Increased vascular calcification promotes arterial stiffness and accelerates cardiovascular morbidity and mortality. Upregulation of the Runx2 (Runt-related transcription factor 2), an essential osteogenic transcription factor for bone formation, in the cardiovascular system has emerged as an important regulator for adverse cellular events that drive cardiovascular pathology. This review discusses the regulatory mechanisms that are critical for Runx2 expression and function and highlights the dynamic and complex cross talks of a wide variety of posttranslational modifications, including phosphorylation, acetylation, ubiquitination, and O-linked β-N-acetylglucosamine modification, in regulating Runx2 stability, cellular localization, and osteogenic transcriptional activity. How the activation of an array of signaling cascades by circulating and local microenvironmental factors upregulates Runx2 in vascular cells and promotes Runx2-mediated osteogenic transdifferentiation of vascular smooth muscle cells and expression of inflammatory cytokines that accelerate macrophage infiltration and vascular osteoclast formation is summarized. Furthermore, the increasing appreciation of a new role of Runx2 upregulation in promoting vascular smooth muscle cell phenotypic switch, and Runx2 modulated by O-linked β-N-acetylglucosamine modification and Runx2-dependent repression of smooth muscle cell-specific gene expression are discussed. Further exploring the regulation of this key osteogenic transcription factor and its new perspectives in the vasculature will provide novel insights into the transcriptional regulation of vascular smooth muscle cell phenotype switch, reprograming, and vascular inflammation that promote the pathogenesis of arteriosclerosis.

Keywords: arteriosclerosis; inflammation; morbidity; mortality; vascular calcification.

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Conflict of interest statement

DISCLOSURES

The authors have no potential conflicts of interests to disclose.

Figures

Figure 1.
Figure 1.. RUNX2 gene and protein structure.
A) RUNX2 gene structure. Two major RUNX2 isoforms are transcribed from the P1 and P2 promoters respectively, indicating by the ATG start codons, which are encoded by exon 1–8 (type II) or exons 2–8 (type I). The DNA binding Runt homology domain (RHD) is encoded by exons 2–5. B) RUNX2 protein structure. In addition to the RHD domain, RUNX2 proteins contain a glutamine/alanine (QA) rich region, a nuclear-localization signal (NLS), a proline/serine/threonine (PST) rich region, a nuclear matrix targeting signal (NMTS), and a C-terminal VWRPY domain for TLE/Groucho interactions.
Figure 2.
Figure 2.. Runx2 interaction with various cytosolic and nuclear proteins that regulate its post-translational modification, cellular localization and stability, and transcriptional activity.
The binding proteins of the Runt-related transcription factor 2 (Runx2) regulate Runx2 posttranslational modifications (PTMs), including phosphorylation, ubiquitination, acetylation and O-GlcNAcylation are shown (top left); Runx2 nuclear translocation, DNA binding and transcriptional activities are highlighted (top right). The key regulators for Runx2 PTMs and Runx2 transactivity are shown in the respective box. In addition, binding of Runx2 to the CBF consensus sequence TGT/cGGT on the target genes, via its Runt-homology domain, regulates the transcription of the target genes (bottom).
Figure 3.
Figure 3.. Upregulation of Runx2 in vascular cells promotes vascular calcification, inflammation, smooth muscle cell phenotypic switch that accelerates arteriosclerosis.
In response to local and circulating stimuli, activation of pro-osteogenic signals induce upregulation of the Runt-related transcription factor 2 (Runx2) and its post-translational modifications (PTMs), which increase Runx2 transcriptional activity. Upregulation of Runx2 in vascular smooth muscle cells (VSMC) induces osteogenic differentiation and VSMC calcification; and increases the expression of inflammatory cytokines that promotes infiltration of macrophages and the differentiation of vascular osteoclasts. In addition, upregulation of Runx2 in VSMC represses the expression of SMC specific marker genes, enhancing SMC phenotypic switch. Ultimately, Runx2-induced molecular and cellular changes in VSMC promotes the development of vascular calcification, atherosclerosis and arterial stiffness.
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