Physiological Concentrations of Calciprotein Particles Trigger Activation and Pro-Inflammatory Response in Endothelial Cells and Monocytes

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Daria Shishkova^1,a, Victoria Markova^1,b, Yulia Markova^1,c, Maxim Sinitsky^1,d, Anna Sinitskaya^1,e, Vera Matveeva^1,f, Evgenia Torgunakova^1,g, Anastasia Lazebnaya^1,h, Alexander Stepanov^1,i, Anton Kutikhin^1,j*

¹Department of Experimental Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, 650002 Kemerovo, Russia

^* To whom correspondence should be addressed.

Received: November 13, 2024; Revised: December 3, 2024; Accepted: December 5, 2024

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Supraphysiological concentrations of calciprotein particles (CPPs), which are indispensable scavengers of excessive Ca²⁺ and PO₄³⁻ ions in blood, induce pro-inflammatory activation of endothelial cells (ECs) and monocytes. Here, we determined physiological levels of CPPs (10 μg/mL calcium, corresponding to 10% increase in Ca²⁺ in the serum or medium) and investigated whether the pathological effects of calcium stress depend on the calcium delivery form, such as Ca²⁺ ions, albumin- or fetuin-centric calciprotein monomers (CPM-A/CPM-F), and albumin- or fetuin-centric CPPs (CPP-A/CPP-F). The treatment with CPP-A or CPP-F upregulated transcription of pro-inflammatory genes (VCAM1, ICAM1, SELE, IL6, CXCL8, CCL2, CXCL1, MIF) and promoted release of pro-inflammatory cytokines (IL-6, IL-8, MCP-1/CCL2, and MIP-3α/CCL20) and pro- and anti-thrombotic molecules (PAI-1 and uPAR) in human arterial ECs and monocytes, although these results depended on the type of cell and calcium-containing particles. Free Ca²⁺ ions and CPM-A/CPM-F induced less consistent detrimental effects. Intravenous administration of CaCl₂, CPM-A, or CPP-A to Wistar rats increased production of chemokines (CX3CL1, MCP-1/CCL2, CXCL7, CCL11, CCL17), hepatokines (hepassocin, fetuin-A, FGF-21, GDF-15), proteases (MMP-2, MMP-3) and protease inhibitors (PAI-1) into the circulation. We concluded that molecular consequences of calcium overload are largely determined by the form of its delivery and CPPs are efficient inducers of mineral stress at physiological levels.

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KEY WORDS: calciprotein particles, calciprotein monomers, calcium ions, calcium stress, mineral stress, endothelial cells, monocytes, endothelial dysfunction, endothelial activation, systemic inflammatory response

DOI: 10.1134/S0006297924604064

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