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Shotgun proteomics analysis of nuclear and mitochondrial from human coronary artery endothelial cells fraction treated with calcioprotein particles

ABSTRACT: Calciprotein particles (CPPs) are indispensable scavengers of excessive Ca2+ and PO43- ions in the blood, being internalized and recycled by liver and spleen macrophages, monocytes, and endothelial cells (ECs). Despite the fact, that CPPs are associated with many cardiovascular diseases and are known to trigger endothelial dysfunction, the exact mechanisms of its recycling by ECs are still poorly studied. Particularly, because of the low resolution of the standard proteomics approach. We assume that CPPs internalization would cause oxidative stress and strong rearrangements in the transcription. Therefore, we performed a shotgun proteomics analysis of nuclear and mitochondrial fraction of human coronary artery endothelial cells (HCAEC) treated with primary (amorphous) or secondary (crystalline) CPPs (CPP-P and CPPs, respectively). Contact: Dr Anton G. Kutikhin, Laboratory of Molecular, Translational and Digital Medicine, Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia (lab head).

INSTRUMENT(S): timsTOF Pro 2

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hcaec Cell

SUBMITTER: Egor Repkin

LAB HEAD: Dr. Anton G. Kutikhin

PROVIDER: PXD047581 | Pride | 2023-12-31

REPOSITORIES: Pride

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Project description:Calciprotein particles (CPPs) represent self-assembling scavengers of excessive Ca2+ and PO43- ions which are formed in the human serum under the guidance of acidic proteins termed mineral chaperones (e.g., fetuin-A and albumin). While protecting the human organism from extraskeletal calcification, circulating CPPs are internalised by Kupffer cells and endothelial cells (ECs) and induce calcium stress upon their dissolution in lysosomes, thereby causing a pro-inflammatory response through the inflammasome-dependent and inflammasome-independent mechanisms. In patients with hyperphosphatemia (e.g., those with end-stage renal disease), a considerable proportion of primary amorphous CPPs transforms into secondary crystallised CPPs which instigate stronger cytokine release and indicate critical depletion of mineral buffering systems. A number of reports documented that serum of patients with chronic kidney disease, arterial hypertension, coronary artery disease, cerebrovascular disease, and autoimmune disorders shows increased CPP generation that reflects uncurbed mineral stress in these clinical scenarios and emphasizes the need in the development of anti-CPP therapies. For the experiments, CPPs are routinely synthesised in vitro by the supersaturation of serum-supplemented cell culture medium with Ca2+ and PO43- ions, as artificially generated CPPs are similar to those isolated from calcified human tissues. Approximate concentration of CPPs in the human blood is 250 particles per µL (2.5 × 108 per L), as measured by fluorescent-labeled bisphosphonate OsteoSense 680EX (IVISense Osteo 680 fluorescent probe). The kinetics of CPP assembling and clearance is far from being fully understood, albeit it evidently depends on the amount of Ca2+ and PO43- ions and acidic serum proteins (especially fetuin-A and albumin), and several reports specified a role of Mg2+ ions, HCO3- ions, and pyrophosphate in these processes as intrinsic Ca2+ antagonists. Although previous studies delineated cytokines overproduced by ECs under CPP treatment (i.e., interleukin-6, interleukin-8, and monocyte chemoattractant protein 1) and itemised other pathological consequences of CPP internalisation (i.e., hampered NO biosynthesis, endothelial-to-mesenchymal transition, and impaired mechanotransduction), a little is known about the proteomic signatures of ECs to calcium stress. Here we for the first time performed an unbiased proteomic profiling of ECs treated with CPPs and revealed relative enrichment of the protein categories related to mitochondrial and lysosomal physiology after the CPP treatment.

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Shotgun proteomics analysis of nuclear and mitochondrial from human coronary artery endothelial cells fraction treated with calcioprotein particles

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