scholarly journals Calciprotein Particles Link Disturbed Mineral Homeostasis with Cardiovascular Disease by Causing Endothelial Dysfunction and Vascular Inflammation

2021 ◽  
Vol 22 (22) ◽  
pp. 12458
Author(s):  
Daria K. Shishkova ◽  
Elena A. Velikanova ◽  
Leo A. Bogdanov ◽  
Maxim Yu. Sinitsky ◽  
Alexander E. Kostyunin ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Endothelial Dysfunction ◽  
Leukocyte Adhesion ◽  
Binding Capacity ◽  
Vascular Inflammation ◽  
Mechanistic Explanation ◽  
High Serum ◽  
Mesenchymal Transition ◽  
Mineral Homeostasis ◽  
Calciprotein Particles

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.

scholarly journals Pathophysiological and clinical significance of mineral homeostasis disorders in the development of cardiovascular disease

2021 ◽  
Vol 6 (2) ◽  
pp. 82-102
Author(s):  
A. G. Kutikhin
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Cardiovascular Death ◽  
Therapeutic Interventions ◽  
Major Adverse Cardiovascular Events ◽  
Formation Mechanisms ◽  
Kidney Transplant Recipients ◽  
Mesenchymal Transition ◽  
Mineral Homeostasis ◽  
Calciprotein Particles

A growing incidence, prevalence, morbidity and mortality from cardiovascular disease dictate an urgent need in identification of its risk factors and their pathogenetic links with coronary artery disease and stroke. Aging of the population is inevitably associated with an increasing prevalence of comorbid conditions. Among them are disorders of mineral homeostasis which, often being neglected, are clearly associated with major adverse cardiovascular events and cardiovascular death. Maintenance of mineral homeostasis in the human body is largely dependent on the formation of calciprotein particles (CPPs) which arise in the blood upon the binding of a mineral chaperone fetuin-A to nascent calcium phosphate crystals, thereby aggregating excessive calcium (Ca2+) and phosphate (PO4 3-), removing them from the bloodstream and preventing extraskeletal calcification. During the circulation, CPPs are internalised by arterial endothelial cells and provoke endothelial dysfunction through endothelial activation, endothelialto-mesenchymal transition and impairment of endothelial mechanotransduction. Animal studies demonstrated that regular intravenous injections of CPPs lead to intimal hyperplasia and adventitial/perivascular inflammation in the absence of any other cardiovascular risk factors, indicating pathophysiological importance of CPPs for cardiovascular disease. Further, a number of clinical studies suggested an association of an augmented serum calcification propensity or elevated CPP count with arterial hypertension, myocardial infarction, chronic brain ischemia, ischemic stroke and cardiovascular death in patients with chronic kidney disease (including those with end-stage renal disease as well as kidney transplant recipients) and individuals with a preserved renal function. Here, we critically discuss the pathophysiological consequences of CPP formation, mechanisms of their pathogenic effects, and potential therapeutic interventions. 

Abstract 368: Family History of Premature Cardiac Events and Sub Clinical Atherosclerosis in Children and Young Adults: A Systematic Review

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Pragya Sinha ◽  
Jamal S Rana ◽  
Ebenezer T Oni ◽  
Ehimen C Aneni ◽  
Roger S Blumenthal ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Young Adults ◽  
Family History ◽  
Endothelial Dysfunction ◽  
Subclinical Atherosclerosis ◽  
Vascular Inflammation ◽  
Positive Family History ◽  
Cardiac Risk Factor ◽  
Children And Young Adults ◽  
The Impact

BACKGROUND The association between a positive family history (PFH) of premature cardiovascular disease (PCVD) and atherosclerosis has been explored in numerous studies. In adults, various studies have confirmed a significant positive correlation between a PFH and PCVD. Scant literature however, focuses on young individuals. Nevertheless, it is important to understand the impact that a PFH has in young people because the foundations of atherosclerosis and adverse cardiac behaviors develop in youth. In this paper, we aimed to systematically review the evidence linking a PFH of PCVD to indirect markers of subclinical atherosclerosis. METHODS The search was conducted on Medline, Web of Science and Embase. ‘Family history’, ‘children/young adults’ and ‘subclinical atherosclerosis’ were the three main concepts used. Increase in mean carotid IMT (cIMT), endothelial dysfunction and vascular inflammation were used as indirect measures of subclinical atherosclerosis. RESULTS 1191 articles were identified in the initial search. 24 papers with 5400 participants were included in the final review. There were five cohort studies and nineteen case control studies from twelve countries. Mean cIMT was found to be significantly increased in those with a PFH by eleven of the fourteen papers reviewed. Endothelial dysfunction, measured by flow mediated dilatation (FMD), was found to be significantly increased in five of the seven included studies. The evidence on vascular inflammation was somewhat inconsistent with only ten of the nineteen studies demonstrating significance. The results tend to suggest that an elevated mean cIMT, as well as a greater degree of endothelial dysfunction are seen in children and young adults with a PFH of PCVD. Moreover, these differences exist in asymptomatic children as young as 8-9 years (4 studies) in the absence of any other cardiac risk factor. DISCUSSION Individuals with a PFH of PCVD have evidence of subclinical atherosclerosis in their youth demonstrating an accelerated tendency to acquire cardiovascular disease. Some of this risk may be attributable to behavioral risk clustering in families. However, a significant proportion of this elevated risk is related solely to a positive family history and needs attention.

Abstract 12375: Vascular Inflammation Evaluated by 18F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography is Associated With Endothelial Dysfunction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Akihiro Honda ◽  
Nobuhiro Tahara ◽  
Atsuko Tahara ◽  
Sachiyo Igata ◽  
Yoshikazu Nitta ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Positron Emission Tomography ◽  
Endothelial Dysfunction ◽  
Pet Imaging ◽  
Carotid Arteries ◽  
Vascular Inflammation ◽  
Emission Tomography ◽  
Percent Change ◽  
Positron Emission ◽  
Fat Volume

Background: Endothelial dysfunction is an initial step for atherosclerotic cardiovascular disease. However, involvement of vascular inflammation in endothelial dysfunction is not fully investigated in humans. We assessed the relationship between endothelial function and vascular inflammation evaluated by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging. Methods and Results: We examined endothelial function and vascular inflammation, which were evaluated by flow-mediated dilation (FMD) of the brachial artery functionally and FDG-PET imaging of carotid arteries, respectively, in 128 subjects (83 males and 45 females; mean age 61.8 ± 10.0 years) who underwent a risk-screening test for cardiovascular disease in Kurume University Hospital. Vascular inflammation of the carotid arteries was measured by blood-normalized standardized uptake value, known as a target-to-background ratio (TBR). Mean percent change in vasodilation (percent change over the baseline values; %FMD) and carotid TBR were 5.60 ± 2.24 % and 1.43 ± 0.22, respectively. %FMD was less in men than in women. In univariate analysis, %FMD was inversely correlated with age (p=0.011), systolic blood pressure (p=0.014), carotid artery maximum intima-media thickness (p=0.014), HbA1c (p=0.020), visceral fat volume (p=0.005), or TBR values (p<0.001). Multiple stepwise regression analysis revealed that age (p=0.034), visceral fat volume (p=0.002), and TBR values (p<0.001) were independently associated with decreased %FMD (R2=0.245). Conclusions: We found here that vascular inflammation in the carotid arteries evaluated by FDG-PET was one of the independent association of decreased %FMD, thus suggesting that vascular inflammation might contribute to endothelial dysfunction in humans.

scholarly journals Calciprotein Particles Cause Endothelial Dysfunction under Flow

2020 ◽  
Vol 21 (22) ◽  
pp. 8802
Author(s):  
Daria Shishkova ◽  
Victoria Markova ◽  
Maxim Sinitsky ◽  
Anna Tsepokina ◽  
Elena Velikanova ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Endothelial Dysfunction ◽  
Mononuclear Cells ◽  
Human Organism ◽  
Peripheral Blood Mononuclear ◽  
Mesenchymal Transition ◽  
Intravenous Injections ◽  
Calciprotein Particles ◽  
Endothelial To Mesenchymal Transition

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.

scholarly journals Endothelial Dysfunction and Inflammation: Immunity in Rheumatoid Arthritis

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
XueZhi Yang ◽  
Yan Chang ◽  
Wei Wei
Keyword(s):  
Rheumatoid Arthritis ◽  
Cardiovascular Disease ◽  
Endothelial Dysfunction ◽  
Inflammatory Process ◽  
Leukocyte Adhesion ◽  
Active Participant ◽  
Endothelial Repair ◽  
Repair Mechanisms ◽  
A Site ◽  
Leukocyte Adhesion Molecules

Inflammation, as a feature of rheumatoid arthritis (RA), leads to the activation of endothelial cells (ECs). Activated ECs induce atherosclerosis through an increased expression of leukocyte adhesion molecules. Endothelial dysfunction (ED) is recognized as a failure of endothelial repair mechanisms. It is also an early preclinical marker of atherosclerosis and is commonly found in RA patients. RA is now established as an independent cardiovascular risk factor, while mechanistic determinants of ED in RA are still poorly understood. An expanding body of study has shown that EC at a site of RA is both active participant and regulator of inflammatory process. Over the last decade, a role for endothelial dysfunction in RA associated with cardiovascular disease (CVD) has been hypothesized. At the same time, several maintenance drugs targeting this phenomenon have been tested, which has promising results. Assessment of endothelial function may be a useful tool to identify and monitor RA patients.

scholarly journals Inflammatory Mechanisms Contributing to Endothelial Dysfunction

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 781
Author(s):  
Panagiotis Theofilis ◽  
Marios Sagris ◽  
Evangelos Oikonomou ◽  
Alexios S. Antonopoulos ◽  
Gerasimos Siasos ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Inflammatory Mediators ◽  
Leukocyte Adhesion ◽  
Vascular Inflammation ◽  
Endothelial Activation ◽  
Nuclear Factor Κb ◽  
Cellular Adhesion ◽  
Cell Integrity ◽  
Atherosclerosis Progression

Maintenance of endothelial cell integrity is an important component of human health and disease since the endothelium can perform various functions including regulation of vascular tone, control of hemostasis and thrombosis, cellular adhesion, smooth muscle cell proliferation, and vascular inflammation. Endothelial dysfunction is encompassed by complex pathophysiology that is based on endothelial nitric oxide synthase uncoupling and endothelial activation following stimulation from various inflammatory mediators (molecular patterns, oxidized lipoproteins, cytokines). The downstream signaling via nuclear factor-κB leads to overexpression of adhesion molecules, selectins, and chemokines that facilitate leukocyte adhesion, rolling, and transmigration to the subendothelial space. Moreover, oscillatory shear stress leads to pro-inflammatory endothelial activation with increased monocyte adhesion and endothelial cell apoptosis, an effect that is dependent on multiple pathways and flow-sensitive microRNA regulation. Moreover, the role of neutrophil extracellular traps and NLRP3 inflammasome as inflammatory mechanisms contributing to endothelial dysfunction has recently been unveiled and is under further investigation. Consequently, and following their activation, injured endothelial cells release inflammatory mediators and enter a pro-thrombotic state through activation of coagulation pathways, downregulation of thrombomodulin, and an increase in platelet adhesion and aggregation owing to the action of von-Willebrand factor, ultimately promoting atherosclerosis progression.

scholarly journals Role of Endothelial Cell–Derived Angptl2 in Vascular Inflammation Leading to Endothelial Dysfunction and Atherosclerosis Progression

2014 ◽  
Vol 34 (4) ◽  
pp. 790-800 ◽  
Author(s):  
Eiji Horio ◽  
Tsuyoshi Kadomatsu ◽  
Keishi Miyata ◽  
Yasumichi Arai ◽  
Kentaro Hosokawa ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Molecular Mechanisms ◽  
Vascular Inflammation ◽  
Nuclear Factor Κb ◽  
Atherosclerosis Progression ◽  
Atheromatous Plaques

Objective— Cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression. Nonetheless, molecular mechanisms underlying this activity remain unclear. Here, we ask whether angiopoietin-like protein 2 (Angptl2), a proinflammatory protein, contributes to vascular inflammation that promotes atherosclerosis progression. Approach and Results— Histological analysis revealed abundant Angptl2 expression in endothelial cells and macrophages infiltrating atheromatous plaques in patients with cardiovascular disease. Angptl2 knockout in apolipoprotein E–deficient mice ( ApoE −/− / Angptl2 −/− ) attenuated atherosclerosis progression by decreasing the number of macrophages infiltrating atheromatous plaques, reducing vascular inflammation. Bone marrow transplantation experiments showed that Angptl2 deficiency in endothelial cells attenuated atherosclerosis development. Conversely, ApoE −/− mice crossed with transgenic mice expressing Angptl2 driven by the Tie2 promoter ( ApoE −/− /Tie2- Angptl2 Tg), which drives Angptl2 expression in endothelial cells but not monocytes/macrophages, showed accelerated plaque formation and vascular inflammation because of increased numbers of infiltrated macrophages in atheromatous plaques. Tie2- Angptl2 Tg mice alone did not develop plaques but exhibited endothelium-dependent vasodilatory dysfunction, likely because of decreased production of endothelial cell–derived nitric oxide. Conversely, Angptl2 −/− mice exhibited less severe endothelial dysfunction than did wild-type mice when fed a high-fat diet. In vitro, Angptl2 activated proinflammatory nuclear factor-κB signaling in endothelial cells and increased monocyte/macrophage chemotaxis. Conclusions— Endothelial cell–derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression.

P717Glucagon-like peptide 1 (GLP-1) improves endothelial dysfunction and vascular inflammation in polymicrobial sepsis induced by cecal ligation and puncture (CLP)

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Steven ◽  
J Helmstaedter ◽  
F Pawelke ◽  
K Filippou ◽  
K Frenies ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Clinical Trials ◽  
Endothelial Dysfunction ◽  
Knockout Mice ◽  
Vascular Inflammation ◽  
Cecal Ligation ◽  
Cecal Ligation And Puncture ◽  
Glucose Levels ◽  
Dpp4 Inhibitor ◽  
Cardioprotective Effects

Abstract Objective Sepsis causes severe hypotension, accompanied by high mortality in the setting of septic shock. LEADER, SUSTAIN-6 and other clinical trials revealed cardioprotective and anti-inflammatory properties of GLP-1 analogs like Liraglutide (Lira). We already demonstrated improved survival by amelioration of disseminated intravasal coagulation (DIC) in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of the GLP-1 degrading enzyme dipeptidylpeptidase-4 (DPP-4). With the present study we aim to investigate the mechanism of protective effects of the GLP-1 analog Lira and the DPP4 inhibitor Linagliptin (Lina) in the clinically relevant sepsis model cecal ligation and puncture (CLP). Methods C57/BL6j and endothelial cell-specific GLP-1 receptor knockout mice (Cdh5crexGLP-1rfl/flmice) were used and sepsis was induced by cecal ligation and puncture (CLP). DPP4 inhibitor (Lina, 5mg/kg/d; 3 days) and GLP-1 analog (Lira, 200μg/kg/d; 3 days) were applied subcutaneously. Aortic vascular function was tested by isometric tension recording. Aorta and heart tissue was used for Western blotting, dot blot and qRT-PCR. Endogenous GLP-1 (7–36 and 9–36) and insulin was determined by ELISA. Blood samples were collected for examination of cell count, oxidative stress and glucose levels. Results Body temperature was increased by CLP and normalized by Lina and Lira. Sham- and Lira- but not Lina-treated septic mice showed low blood glucose levels compared to healthy controls. Acetylcholine-induced (endothelium-dependent) vascular relaxation in aorta was impaired by CLP. This was accompanied by vascular inflammation and elevation of IL-6, iNOS, ICAM-1, and TNF-alpha mRNA levels in aortic tissue. Vascular, cardiac and whole blood oxidative stress were increased by CLP. Furthermore, we detected higher levels of IL-6, 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-NHE) in plasma of CLP animals. Lina and Lira reduced oxidative stress and vascular inflammation, which was accompanied by improved endothelial function. In addition, CLP treatment in endothelial specific knockout mice of the GLP-1r strongly induced mortality compared to WT mice, with the effect being strongest in the Lira-treated group. Conclusion The present study demonstrates that Lina (DPP4 inhibitor) and the GLP-1 analog Lira ameliorate sepsis-induced endothelial dysfunction by reduction of vascular inflammation and oxidative stress. Clinical trials like LEADER and SUSTAIN-6 proved that GLP-1 analogs like Lira have cardioprotective effects in T2DM patients. The present study, performed in a clinically relevant model of polymicrobial sepsis, reveals that the known cardioprotective effects of GLP-1 might be translated to other diseases which affect the cardiovascular system like sepsis, underlining the potent anti-inflammatory effects of GLP-1 analogs.

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