Myeloid cell-specific ablation of Runx2 gene exacerbates post-infarct cardiac remodeling

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Immunology

Background:

• Runt-related transcription factor 2 (Runx2) is a known regulator of osteoblast differentiation and is implicated in vascular calcification.
• The specific role of Runx2 in maintaining cardiac homeostasis and its function post-myocardial infarction (MI) have remained largely uncharacterized.

Purpose of the Study:

• To investigate the role of Runx2 in cardiac remodeling following myocardial infarction (MI).
• To determine the cellular source and functional significance of Runx2 in the post-MI cardiac environment.

Main Methods:

• Analysis of Runx2 mRNA and protein expression in murine hearts after MI.
• Generation and utilization of myeloid cell-specific Runx2 deficient (CKO) mice subjected to MI.
• Assessment of cardiac function, fibrosis, capillary density, and gene expression profiles (RNA-sequencing) in CKO and control mice post-MI.
• In vitro assays using conditioned media from myeloid cells to evaluate endothelial cell function.

Main Results:

• Runx2 expression was upregulated in murine hearts post-MI, predominantly in infiltrating myeloid cells, particularly macrophages.
• Myeloid cell-specific Runx2 deficiency (CKO) led to exacerbated cardiac dysfunction, increased ventricular weight/tibia length ratio, and enhanced cardiac fibrosis with elevated collagen 1a1 expression.
• CKO mice exhibited reduced capillary density and impaired pro-angiogenic factor expression in macrophages, suggesting a role for Runx2 in regulating endothelial cell function and angiogenesis.

Conclusions:

• Runx2-expressing myeloid cells infiltrate the post-infarct myocardium.
• These Runx2-positive myeloid cells play a protective role in preventing adverse cardiac remodeling after MI.
• Runx2 contributes to cardiac homeostasis post-MI, at least partially, by modulating endothelial cell function and promoting angiogenesis.