Calciprotein Particles: Balancing Mineral Homeostasis and Vascular Pathology.
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ABSTRACT:
SUBMITTER: Kutikhin AG
PROVIDER: S-EPMC8057528 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
Publications
Calciprotein Particles: Balancing Mineral Homeostasis and Vascular Pathology.
Kutikhin Anton G AG Feenstra Lian L Kostyunin Alexander E AE Yuzhalin Arseniy E AE Hillebrands Jan-Luuk JL Krenning Guido G
Arteriosclerosis, thrombosis, and vascular biology 20210311 5
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Project description:An association between high serum calcium/phosphate and cardiovascular events or death is well-established. However, a mechanistic explanation of this correlation is lacking. Here, we examined the role of calciprotein particles (CPPs), nanoscale bodies forming in the human blood upon its supersaturation with calcium and phosphate, in cardiovascular disease. The serum of patients with coronary artery disease or cerebrovascular disease displayed an increased propensity to form CPPs in combination with elevated ionised calcium as well as reduced albumin levels, altogether indicative of reduced Ca2+-binding capacity. Intravenous administration of CPPs to normolipidemic and normotensive Wistar rats provoked intimal hyperplasia and adventitial/perivascular inflammation in both balloon-injured and intact aortas in the absence of other cardiovascular risk factors. Upon the addition to primary human arterial endothelial cells, CPPs induced lysosome-dependent cell death, promoted the release of pro-inflammatory cytokines, stimulated leukocyte adhesion, and triggered endothelial-to-mesenchymal transition. We concluded that CPPs, which are formed in the blood as a result of altered mineral homeostasis, cause endothelial dysfunction and vascular inflammation, thereby contributing to the development of cardiovascular disease.
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Project description:The formation of fetuin-A-containing calciprotein particles (CPP) may facilitate the clearance of calcium phosphate nanocrystals from the extracellular fluid. These crystals may otherwise seed extra-osseous mineralization. Fetuin-A is a partially phosphorylated glycoprotein that plays a critical role in stabilizing these particles, inhibiting crystal growth and aggregation. CPP removal is thought to be predominantly mediated by cells of the reticuloendothelial system via type I and type II class A scavenger receptor (SR-AI/II). Naked calcium phosphate crystals are known to stimulate macrophages and other cell types in vitro, but little is known of the effect of CPP on these cells. We report here, for the first time, that CPP induce expression and secretion of tumour necrosis factor (TNF)-α, interleukin (IL)-1β in murine RAW 264.7 macrophages. Importantly, however, CPP induced significantly lower cytokine secretion than hydroxyapatite (HAP) crystals of equivalent size and calcium content. Furthermore, CPP only had a modest effect on macrophage viability and apoptosis, even at very high levels, compared to HAP crystals, which were strongly pro-apoptotic at much lower levels. Fetuin-A phosphorylation was found to modulate the effect of CPP on cytokine secretion and apoptosis, but not uptake via SR-AI/II. Prolonged exposure of macrophages to CPP was found to result in up-regulated expression of SR-AI/II. CPP formation may help protect against some of the pro-inflammatory and harmful effects of calcium phosphate nanocrystals, perhaps representing a natural defense system for calcium mineral stress. However, in pathological states where production exceeds clearance capacity, these particles may still stimulate pro-inflammatory and pro-apoptotic cascades in macrophages, which may be important in the pathogenesis of vascular calcification.
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Project description:Calciprotein particles (CPPs), which increasingly arise in the circulation during the disorders of mineral homeostasis, represent a double-edged sword protecting the human organism from extraskeletal calcification but potentially causing endothelial dysfunction. Existing models, however, failed to demonstrate the detrimental action of CPPs on endothelial cells (ECs) under flow. Here, we applied a flow culture system, where human arterial ECs were co-incubated with CPPs for 4 h, and a normolipidemic and normotensive rat model (10 daily intravenous injections of CPPs) to simulate the scenario occurring in vivo in the absence of confounding cardiovascular risk factors. Pathogenic effects of CPPs were investigated by RT-qPCR and Western blotting profiling of the endothelial lysate. CPPs were internalised within 1 h of circulation, inducing adhesion of peripheral blood mononuclear cells to ECs. Molecular profiling revealed that CPPs stimulated the expression of pro-inflammatory cell adhesion molecules VCAM1 and ICAM1 and upregulated transcription factors of endothelial-to-mesenchymal transition (Snail, Slug and Twist1). Furthermore, exposure to CPPs reduced the production of atheroprotective transcription factors KLF2 and KLF4 and led to YAP1 hypophosphorylation, potentially disturbing the mechanisms responsible for the proper endothelial mechanotransduction. Taken together, our results suggest the ability of CPPs to initiate endothelial dysfunction at physiological flow conditions.
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Project description:BACKGROUND:The size of secondary calciprotein particles (CPP2) and the speed of transformation (T50) from primary calciprotein particles (CPP1) to CPP2 in serum may be associated with vascular calcification (VC) in patients with chronic kidney disease (CKD). METHODS:We developed a high throughput, microplate-based assay using dynamic light scattering (DLS) to measure the transformation of CPP1 to CPP2, hydrodynamic radius (Rh) of CPP1 and CPP2, T50 and aggregation of CPP2. We used this DLS assay to test the hypothesis that a large Rh of CPP2 and/or a fast T50 are associated with VC in 45 participants with CKD Stages 4-5 (22 without VC and 23 with VC) and 17 healthy volunteers (HV). VC was defined as a Kauppila score >6 or an Adragao score ≥3. RESULTS:CKD participants with VC had larger cumulants Rh of CPP2 {370 nm [interquartile range (IQR) 272-566]} compared with CKD participants without VC [212 nm (IQR 169-315)] and compared with HV [168 nm (IQR 145-352), P < 0.01 for each]. More CPP2 were in aggregates in CKD participants with VC than those without VC (70% versus 36%). The odds of having VC increased by 9% with every 10 nm increase in the Rh of CPP2, after adjusting for age, diabetes, serum calcium and phosphate [odds ratio 1.09, 95% confidence interval (CI) 1.03, 1.16, P = 0.005]. The area under the receiver operating characteristic curve for VC of CPP2 size was 0.75 (95% CI 0.60, 0.90). T50 was similar in CKD participants with and without VC, although both groups had a lower T50 than HV. CONCLUSIONS:Rh of CPP2, but not T50, is independently associated with VC in patients with CKD Stages 4-5.
| S-EPMC6545469 | biostudies-literature
Project description:Calciprotein particles (CPPs), colloidal mineral-protein nanoparticles, have emerged as potential mediators of phosphate toxicity in dialysis patients, with putative links to vascular calcification, endothelial dysfunction and inflammation. We hypothesized that phosphate binder therapy with sucroferric oxyhydroxide (SO) would reduce endogenous CPP levels and attenuate pro-calcific and pro-inflammatory effects of patient serum towards human vascular cells in vitro. This secondary analysis of a randomised controlled crossover study compared the effect of 2-week phosphate binder washout with high-dose (2000 mg/day) and low-dose (250 mg/day) SO therapy in 28 haemodialysis patients on serum CPP levels, inflammatory cytokine/chemokine arrays and human aortic smooth muscle cell (HASMC) and coronary artery endothelial cell (HCAEC) bioassays. In our cohort (75% male, 62 ± 12 years) high-dose SO reduced primary (amorphous) and secondary (crystalline) CPP levels {-62% [95% confidence interval (CI) -76 to -44], P < .0001 and -38% [-62 to -0.14], P < .001, respectively} compared with washout. Nine of 14 plasma cytokines/chemokines significantly decreased with high-dose SO, with consistent reductions in interleukin-6 (IL-6) and IL-8. Exposure of HASMC and HCAEC cultures to serum of SO-treated patients reduced calcification and markers of activation (IL-6, IL-8 and vascular cell adhesion protein 1) compared with washout. Serum-induced HASMC calcification and HCAEC activation was ameliorated by removal of the CPP-containing fraction from patient sera. Effects of CPP removal were confirmed in an independent cohort of chronic kidney disease patients. High-dose SO reduced endogenous CPP formation in dialysis patients and yielded serum with attenuated pro-calcific and inflammatory effects in vitro.
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Project description:IntroductionCalciprotein particles (CPPs) are potentially modifiable mediators of phosphate toxicity in patients with kidney disease. We compared the effects of calcium carbonate (CC) and the non-calcium-based phosphate binder sevelamer on CPP levels in patients undergoing hemodialysis (HD). We hypothesized that treatment with sevelamer would achieve greater reductions in amorphous calcium phosphate-containing CPP (CPP-1) and hydroxyapatite-containing CPP (CPP-2) owing to reduced calcium loading and anti-inflammatory pleiotropic effects.MethodsWe conducted an open-label, randomized controlled trial (RCT) in which 31 stable prevalent HD patients were allocated to receive either sevelamer hydrochloride (SH), sevelamer carbonate (SC), or CC for 24 weeks. Dual primary endpoints were the between groups differences in serum CPP-1 and CPP-2 levels at 24 weeks in SH + SC-treated versus CC-treated patients. Effects on aortic pulse wave velocity (aPWV), inflammatory cytokines (interleukin-6 and -8), and effects across individual treatment arms were also assessed.ResultsSerum CPP-1, but not CPP-2, levels were lower in those randomly assigned to the sevelamer (SH + SC) group compared with the CC group at 24 weeks (-70%, 95% confidence interval [CI] -90% to -15%, P = 0.02). In subgroup analysis, this effect was confined to those receiving SC (-83.4%, 95% CI -95.7% to -36.8%, P = 0.01). aPWV and interleukin-8 levels were also lower in those who received sevelamer compared with CC at 24 weeks (-2.0 m/s, 95% CI -2.9 to -1.1; -57%, 95% CI -73% to -30%, respectively, both P = 0.01). Conventional markers of mineral metabolism remained stable across all treatment groups.DiscussionCompared with treatment with CC, use of sevelamer for 24 weeks was associated with lower serum CPP-1 levels and a reduction in aPWV and systemic inflammation.
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Project description:Patients with chronic inflammatory diseases (CID) experience accelerated loss of bone mineral density, which is often accompanied by increased vascular calcification. These disturbances can be attenuated by therapies for inflammation, such as the tumor necrosis factor inhibitor infliximab. Calciprotein particles (CPP) are circulating colloidal aggregates of calcium and phosphate together with the mineral-binding protein fetuin-A, which have emerged as potential mediators of vascular calcification. The precise origins of serum CPP are unclear, but bone turnover may be an important source. In this longitudinal observational study, we studied patients with CID undergoing treatment with infliximab to assess the temporal relationship between bone turnover and circulating CPP. Ten patients with active CID receiving infliximab induction therapy and an additional 3 patients with quiescent CID on maintenance infliximab therapy were studied for 8 weeks with repeated measures of bone turnover markers as well as CPP (calciprotein monomers [CPM], primary CPP [CPP-I], and secondary CPP [CPP-II]). Therapeutic response was appraised using validated disease activity scores. At baseline, those with active CID had elevated markers of bone resorption and suppressed bone formation markers as well as higher CPM and CPP-I compared with those with quiescent CID. In responders, there was an early but transient reduction in resorption markers by week 1, but a more sustained increase in bone formation markers compared with non-responders at week 8. This was accompanied by reductions in CPM (β = -6.5 × 103 AU [95% CI -11.1, -1.8], p = 0.006) and CPP-I (β = -23.4 × 104 particles/mL [95% CI -34.8, -11.9], p < 0.001). In contrast, no significant changes in any markers were observed in non-responders or those receiving maintenance therapy. Thus, CPP have a dynamic association with changes in bone turnover in response to infliximab therapy, adding to accumulating evidence of the role of bone as a determinant of systemic levels. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Project description:BackgroundPhosphate (Pi) toxicity is a strong determinant of vascular calcification development in chronic kidney disease (CKD). Magnesium (Mg2+) may improve cardiovascular risk via vascular calcification. The mechanism by which Mg2+ counteracts vascular calcification remains incompletely described. Here we investigated the effects of Mg2+ on Pi and secondary crystalline calciprotein particles (CPP2)-induced calcification and crystal maturation.MethodsVascular smooth muscle cells (VSMCs) were treated with high Pi or CPP2 and supplemented with Mg2+ to study cellular calcification. The effect of Mg2+ on CPP maturation, morphology and composition was studied by medium absorbance, electron microscopy and energy dispersive spectroscopy. To translate our findings to CKD patients, the effects of Mg2+ on calcification propensity (T50) were measured in sera from CKD patients and healthy controls.ResultsMg2+ supplementation prevented Pi-induced calcification in VSMCs. Mg2+ dose-dependently delayed the maturation of primary CPP1 to CPP2 in vitro. Mg2+ did not prevent calcification and associated gene and protein expression when added to already formed CPP2. Confirmatory experiments in human serum demonstrated that the addition of 0.2 mmol/L Mg2+ increased T50 from healthy controls by 51 ± 15 min (P < 0.05) and CKD patients by 44 ± 13 min (P < 0.05). Each further 0.2 mmol/L addition of Mg2+ led to further increases in both groups.ConclusionsOur results demonstrate that crystalline CPP2 mediates Pi-induced calcification in VSMCs. In vitro, Mg2+ delays crystalline CPP2 formation and thereby prevents Pi-induced calcification.
| S-EPMC7203562 | biostudies-literature
Project description:Calciprotein particles (CPPs) are indispensable scavengers of excessive Ca2+ and PO43- ions in blood, being internalised and recycled by liver and spleen macrophages, monocytes, and endothelial cells (ECs). Here, we performed a pathway enrichment analysis of cellular compartment-specific proteomes in primary human coronary artery ECs (HCAEC) and human internal thoracic artery ECs (HITAEC) treated with primary (amorphous) or secondary (crystalline) CPPs (CPP-P and CPPs, respectively). Exposure to CPP-P and CPP-S induced notable upregulation of: (1) cytokine- and chemokine-mediated signaling, Ca2+-dependent events, and apoptosis in cytosolic and nuclear proteomes; (2) H+ and Ca2+ transmembrane transport, generation of reactive oxygen species, mitochondrial outer membrane permeabilisation, and intrinsic apoptosis in the mitochondrial proteome; (3) oxidative, calcium, and endoplasmic reticulum (ER) stress, unfolded protein binding, and apoptosis in the ER proteome. In contrast, transcription, post-transcriptional regulation, translation, cell cycle, and cell-cell adhesion pathways were underrepresented in cytosol and nuclear compartments, whilst biosynthesis of amino acids, mitochondrial translation, fatty acid oxidation, pyruvate dehydrogenase activity, and energy generation were downregulated in the mitochondrial proteome of CPP-treated ECs. Differentially expressed organelle-specific pathways were coherent in HCAEC and HITAEC and between ECs treated with CPP-P or CPP-S. Proteomic analysis of mitochondrial and nuclear lysates from CPP-treated ECs confirmed bioinformatic filtration findings.
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Project description:Calciprotein particles (CPPs) represent an inherent mineral buffering system responsible for the scavenging of excessive Ca2+ and PO43- 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, Ca2+ 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.
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