Extracellular Histones Promote Calcium Phosphate-Dependent Calcification in Mouse Vascular Smooth Muscle Cells

Tomonori Hoshino; Davood Kharaghani; Shohei Kohno

doi:10.1093/jb/mvae011

Extracellular Histones Promote Calcium Phosphate-Dependent Calcification in Mouse Vascular Smooth Muscle Cells

J Biochem. 2024 Feb 1:mvae011. doi: 10.1093/jb/mvae011. Online ahead of print.

Authors

Tomonori Hoshino^{1

2}, Davood Kharaghani^{1

3}, Shohei Kohno^{1

4}

Affiliations

¹ Department of Calcified Tissue Biology, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima 734-8553, Japan.
² Neuroprotection Research Laboratories, Departments of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
³ Nanoscience and Advanced Materials Center, Environmental and Occupational Health Sciences Institute (EOHSI) and School of Public Health, Rutgers-New Brunswick, The State University of New Jersey, Piscataway, NJ 08854, USA.
⁴ Department of Maxillofacial Anatomy and Neuroscience, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8553, Japan.

PMID: 38302575
DOI: 10.1093/jb/mvae011

Abstract

Vascular calcification, a major risk factor for cardiovascular events, is associated with a poor prognosis in chronic kidney disease (CKD) patients. This process is often associated with the transformation of vascular smooth muscle cells (VSMCs) into cells with osteoblast-like characteristics. Damage-associated molecular patterns (DAMPs), such as extracellular histones released from damaged or dying cells, are suspected to accumulate at calcification sites. To investigate the potential involvement of DAMPs in vascular calcification, we assessed the impact of externally added histones (extracellular histones) on calcium and inorganic phosphate-induced calcification in mouse VSMCs. Our study found that extracellular histones intensified calcification. We also observed that the histones decreased the expression of VSMC marker genes, while simultaneously increasing the expression of osteoblast marker genes. Additionally, histones treated with DNase I, which degrades dsDNA, attenuated this calcification, compared with the non-treated histones, suggesting a potential involvement of dsDNA in this process. Elevated levels of dsDNA were also detected in the serum of CKD model mice, underlining its potential role in vascular calcification in CKD. Our findings suggest that extracellular histones could play a pivotal role in the vascular calcification observed in CKD.

Keywords: chronic kidney disease (CKD); damage-associated molecular patterns (DAMPs); extracellular histones; vascular calcification; vascular smooth muscle cells (VSMCs).