Calciprotein Particles Cause Physiologically Significant Pro-Inflammatory Response in Endothelial Cells and Systemic Circulation
Calciprotein particles (CPPs) represent an inherent mineral buffering system responsible for the scavenging of excessive Ca<sup>2+</sup> and PO<sub>4</sub><sup>3−</sup> ions in order to prevent extraskeletal calcification, although contributing to the development...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/23/14941 |
| _version_ | 1797463113117728768 |
|---|---|
| author | Daria Shishkova Arseniy Lobov Bozhana Zainullina Vera Matveeva Victoria Markova Anna Sinitskaya Elena Velikanova Maxim Sinitsky Anastasia Kanonykina Yulia Dyleva Anton Kutikhin |
| author_facet | Daria Shishkova Arseniy Lobov Bozhana Zainullina Vera Matveeva Victoria Markova Anna Sinitskaya Elena Velikanova Maxim Sinitsky Anastasia Kanonykina Yulia Dyleva Anton Kutikhin |
| author_sort | Daria Shishkova |
| collection | DOAJ |
| description | Calciprotein particles (CPPs) represent an inherent mineral buffering system responsible for the scavenging of excessive Ca<sup>2+</sup> and PO<sub>4</sub><sup>3−</sup> ions in order to prevent extraskeletal calcification, although contributing to the development of endothelial dysfunction during the circulation in the bloodstream. Here, we performed label-free proteomic profiling to identify the functional consequences of CPP internalisation by endothelial cells (ECs) and found molecular signatures of significant disturbances in mitochondrial and lysosomal physiology, including oxidative stress, vacuolar acidification, accelerated proteolysis, Ca<sup>2+</sup> cytosolic elevation, and mitochondrial outer membrane permeabilisation. Incubation of intact ECs with conditioned medium from CPP-treated ECs caused their pro-inflammatory activation manifested by vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1) upregulation and elevated release of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1/ C-C motif ligand 2 (MCP-1/CCL2). Among the blood cells, monocytes were exclusively responsible for CPP internalisation. As compared to the co-incubation of donor blood with CPPs in the flow culture system, intravenous administration of CPPs to Wistar rats caused a considerably higher production of chemokines, indicating the major role of monocytes in CPP-triggered inflammation. Upregulation of sICAM-1 and IL-8 also suggested a notable contribution of endothelial dysfunction to systemic inflammatory response after CPP injections. Collectively, our results demonstrate the pathophysiological significance of CPPs and highlight the need for the development of anti-CPP therapies. |
| first_indexed | 2024-03-09T17:46:02Z |
| format | Article |
| id | doaj.art-f83fc006a2574fe7ad02047b4a2a0349 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:46:02Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f83fc006a2574fe7ad02047b4a2a03492023-11-24T11:10:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123231494110.3390/ijms232314941Calciprotein Particles Cause Physiologically Significant Pro-Inflammatory Response in Endothelial Cells and Systemic CirculationDaria Shishkova0Arseniy Lobov1Bozhana Zainullina2Vera Matveeva3Victoria Markova4Anna Sinitskaya5Elena Velikanova6Maxim Sinitsky7Anastasia Kanonykina8Yulia Dyleva9Anton Kutikhin10Department of Experimental Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, 6 Sosnovy Boulevard, 650002 Kemerovo, RussiaLaboratory of Regenerative Biomedicine, Institute of Cytology of the RAS, 4 Tikhoretskiy Prospekt, 194064 St. Petersburg, RussiaCentre for Molecular and Cell Technologies, St. Petersburg State University, Universitetskaya Embankment, 7/9, 199034 St. Petersburg, RussiaDepartment of Experimental Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, 6 Sosnovy Boulevard, 650002 Kemerovo, RussiaDepartment of Experimental Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, 6 Sosnovy Boulevard, 650002 Kemerovo, RussiaDepartment of Experimental Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, 6 Sosnovy Boulevard, 650002 Kemerovo, RussiaDepartment of Experimental Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, 6 Sosnovy Boulevard, 650002 Kemerovo, RussiaDepartment of Experimental Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, 6 Sosnovy Boulevard, 650002 Kemerovo, RussiaDepartment of Experimental Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, 6 Sosnovy Boulevard, 650002 Kemerovo, RussiaDepartment of Experimental Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, 6 Sosnovy Boulevard, 650002 Kemerovo, RussiaDepartment of Experimental Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, 6 Sosnovy Boulevard, 650002 Kemerovo, RussiaCalciprotein particles (CPPs) represent an inherent mineral buffering system responsible for the scavenging of excessive Ca<sup>2+</sup> and PO<sub>4</sub><sup>3−</sup> ions in order to prevent extraskeletal calcification, although contributing to the development of endothelial dysfunction during the circulation in the bloodstream. Here, we performed label-free proteomic profiling to identify the functional consequences of CPP internalisation by endothelial cells (ECs) and found molecular signatures of significant disturbances in mitochondrial and lysosomal physiology, including oxidative stress, vacuolar acidification, accelerated proteolysis, Ca<sup>2+</sup> cytosolic elevation, and mitochondrial outer membrane permeabilisation. Incubation of intact ECs with conditioned medium from CPP-treated ECs caused their pro-inflammatory activation manifested by vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1) upregulation and elevated release of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1/ C-C motif ligand 2 (MCP-1/CCL2). Among the blood cells, monocytes were exclusively responsible for CPP internalisation. As compared to the co-incubation of donor blood with CPPs in the flow culture system, intravenous administration of CPPs to Wistar rats caused a considerably higher production of chemokines, indicating the major role of monocytes in CPP-triggered inflammation. Upregulation of sICAM-1 and IL-8 also suggested a notable contribution of endothelial dysfunction to systemic inflammatory response after CPP injections. Collectively, our results demonstrate the pathophysiological significance of CPPs and highlight the need for the development of anti-CPP therapies.https://www.mdpi.com/1422-0067/23/23/14941calciprotein particlescalcium stressendothelial cellsproteomic profilingmitochondrialysosomes |
| spellingShingle | Daria Shishkova Arseniy Lobov Bozhana Zainullina Vera Matveeva Victoria Markova Anna Sinitskaya Elena Velikanova Maxim Sinitsky Anastasia Kanonykina Yulia Dyleva Anton Kutikhin Calciprotein Particles Cause Physiologically Significant Pro-Inflammatory Response in Endothelial Cells and Systemic Circulation International Journal of Molecular Sciences calciprotein particles calcium stress endothelial cells proteomic profiling mitochondria lysosomes |
| title | Calciprotein Particles Cause Physiologically Significant Pro-Inflammatory Response in Endothelial Cells and Systemic Circulation |
| title_full | Calciprotein Particles Cause Physiologically Significant Pro-Inflammatory Response in Endothelial Cells and Systemic Circulation |
| title_fullStr | Calciprotein Particles Cause Physiologically Significant Pro-Inflammatory Response in Endothelial Cells and Systemic Circulation |
| title_full_unstemmed | Calciprotein Particles Cause Physiologically Significant Pro-Inflammatory Response in Endothelial Cells and Systemic Circulation |
| title_short | Calciprotein Particles Cause Physiologically Significant Pro-Inflammatory Response in Endothelial Cells and Systemic Circulation |
| title_sort | calciprotein particles cause physiologically significant pro inflammatory response in endothelial cells and systemic circulation |
| topic | calciprotein particles calcium stress endothelial cells proteomic profiling mitochondria lysosomes |
| url | https://www.mdpi.com/1422-0067/23/23/14941 |
| work_keys_str_mv | AT dariashishkova calciproteinparticlescausephysiologicallysignificantproinflammatoryresponseinendothelialcellsandsystemiccirculation AT arseniylobov calciproteinparticlescausephysiologicallysignificantproinflammatoryresponseinendothelialcellsandsystemiccirculation AT bozhanazainullina calciproteinparticlescausephysiologicallysignificantproinflammatoryresponseinendothelialcellsandsystemiccirculation AT veramatveeva calciproteinparticlescausephysiologicallysignificantproinflammatoryresponseinendothelialcellsandsystemiccirculation AT victoriamarkova calciproteinparticlescausephysiologicallysignificantproinflammatoryresponseinendothelialcellsandsystemiccirculation AT annasinitskaya calciproteinparticlescausephysiologicallysignificantproinflammatoryresponseinendothelialcellsandsystemiccirculation AT elenavelikanova calciproteinparticlescausephysiologicallysignificantproinflammatoryresponseinendothelialcellsandsystemiccirculation AT maximsinitsky calciproteinparticlescausephysiologicallysignificantproinflammatoryresponseinendothelialcellsandsystemiccirculation AT anastasiakanonykina calciproteinparticlescausephysiologicallysignificantproinflammatoryresponseinendothelialcellsandsystemiccirculation AT yuliadyleva calciproteinparticlescausephysiologicallysignificantproinflammatoryresponseinendothelialcellsandsystemiccirculation AT antonkutikhin calciproteinparticlescausephysiologicallysignificantproinflammatoryresponseinendothelialcellsandsystemiccirculation |