Research on Vascular Calcification in Cardiovascular Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Cardiovascular System".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 40667

Special Issue Editors

Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands
Interests: vascular smooth muscle cells; vascular calcification; vitamin K; Matrix Gla protein; atherosclerosis; aneurysm
Division of Renal Medicine, Department of Clinical Science, Intervention and Technology Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
Interests: identification; prevention and treatment of nutritional; metabolic; hormonal; cardiovascular and other alterations in chronic kidney disease patients that contribute to premature aging and increased morbimortality
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Special Issue Information

Dear Colleagues,

The ageing population continues to suffer from its primary killer: cardiovascular disease (CVD). Despite recent advances in interventional medicinal and surgical therapies, coronary artery disease is still the single most common cause of death. Modern cardiology is focused on techniques designed to restore blood flow in obstructed arteries. However, this reactive strategy is unable to save the life of approximately ~1.3 million patients per year that succumb to the initial coronary event. And although pharmacotherapy with agents such as antithrombotics and statins has proven to lower the risk of future CV events, it does not represent a remedy for all.

Vascular calcification (VC) has proven to play an important role in cardiovascular morbidity and mortality (and stroke). Indeed, vascular calcification plays a role in 4 out of the top 10 causes of death as postulated by the WHO. Previously thought to be a passive process, it is now clear vascular calcification is a highly regulated process involving many different factors.

Vascular calcification might present in different ways: it can occur in the vascular intima as well as in the media and it may have different shapes and sizes. Additionally, it can present in the aortic valves where it is related to aortic valve stenosis. Recent data suggest that microcalcification can have a destabilising effect on atherosclerotic plaques, whereas the role of large calcification plaque-stability is largely unknown. Rupture of an unstable (vulnerable) plaque is widely recognised as the principal precipitant of AMI and stroke and an important cause of death. Calcification of the medial vessel wall is strongly associated with hypertension and aneurysm. Comorbidities such as diabetes mellitus and chronic kidney disease fuel the vascular calcification process and are associated with increased cardiovascular mortality. Here, calcifying protein particles (CPPs) seem to play a major role.

Effective interventions to prevent and/or reverse vulnerable plaque formation and/or its rupture are lacking. This is largely due to the absence of insights in calcification pathophysiology and the translation thereof into cost-effective interventions. This illustrates the high promise of VC as new target for diagnosis and intervention in cardiovascular diseases, and a comprehensive view on initiation and progression of calcification and its impact on cardiovascular disease remains elusive. More importantly even, there is an urgent need to translate experimental findings into adequate diagnostic, preventive and therapeutic solutions.

The present Special Issue aims to summarize some of the newest advances in vascular calcification in CVD. We aim to highlight the key involvement of resident and infiltrated cells in the pathophysiology of CVD, including reviews focused on specific cell types. Also, we aim for biological, chemical, and medical expertise supporting a translational approach that will enable development of new or the evaluation of existing imaging modalities for the identification of vascular calcification for better risk prediction and benefit to patients. Finally, we aim for novel insights in treatment of – including vascular senescence – that lie behind the processes of calcification and altering of functionality of vascular tissue.

Prof. Dr. Leon Schurgers
Dr. Peter Stenvinkel
Guest Editors

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Keywords

  • cardiovascular system
  • cardiovascular disease
  • vascular calcification
  • calcifying protein particles (CPP)
  • chronic kidney disease
  • diabetes mellitus
  • matrix gla protein
  • vitamin K
  • hypertension
  • atrial fibrillation
  • monckebergssclerosis
  • medial calcifciation
  • atherosclerosis
  • thrombosis
  • coagulation
  • (myo)fibroblasts
  • pericytes
  • endothelium
  • vascular smooth muscle cells
  • macrophages
  • platelets
  • imaging
  • MSCT
  • NaF18

Published Papers (12 papers)

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Research

Jump to: Review

22 pages, 3983 KiB  
Article
Implications of Senescent Cell Burden and NRF2 Pathway in Uremic Calcification: A Translational Study
by Jonas Laget, Sam Hobson, Karen Muyor, Flore Duranton, Irene Cortijo, Piotr Bartochowski, Bernard Jover, Anne-Dominique Lajoix, Magnus Söderberg, Thomas Ebert, Peter Stenvinkel, Àngel Argilés, Karolina Kublickiene and Nathalie Gayrard
Cells 2023, 12(4), 643; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12040643 - 17 Feb 2023
Cited by 2 | Viewed by 1608
Abstract
Increased senescent cell burden and dysregulation of the nuclear factor erythroid 2–related factor 2 (NRF2) pathway have been associated with numerous age-related pathologies; however, their role in promoting vascular calcification (VC) in chronic kidney disease (CKD) has yet to be determined. We investigated [...] Read more.
Increased senescent cell burden and dysregulation of the nuclear factor erythroid 2–related factor 2 (NRF2) pathway have been associated with numerous age-related pathologies; however, their role in promoting vascular calcification (VC) in chronic kidney disease (CKD) has yet to be determined. We investigated whether senescence and NRF2 pathways may serve as drivers of uremia-induced VC using three complementary approaches: a novel model of induced VC in 5/6-nephrectomized rats supplemented with high phosphate and vitamin D; epigastric arteries from CKD patients with established medial calcification; and vascular smooth muscle cells (VSMCs) incubated with uremic serum. Expression of p16Ink4a and p21Cip1, as well as γ-H2A-positive cells, confirmed increased senescent cell burden at the site of calcium deposits in aortic sections in rats, and was similarly observed in calcified epigastric arteries from CKD patients through increased p16Ink4a expression. However, uremic serum-induced VSMC calcification was not accompanied by senescence. Expression of NRF2 and downstream genes, Nqo1 and Sod1, was associated with calcification in uremic rats, while no difference was observed between calcified and non-calcified EAs. Conversely, in vitro uremic serum-driven VC was associated with depleted NRF2 expression. Together, our data strengthen the importance of senescence and NRF2 pathways as potential therapeutic options to combat VC in CKD. Full article
(This article belongs to the Special Issue Research on Vascular Calcification in Cardiovascular Disease)
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23 pages, 6941 KiB  
Article
1,8-Cineole Affects Agonists-Induced Platelet Activation, Thrombus Formation and Haemostasis
by Kahdr A. Alatawi, Divyashree Ravishankar, Pabitra H. Patra, Alexander P. Bye, Alexander R. Stainer, Ketan Patel, Darius Widera and Sakthivel Vaiyapuri
Cells 2021, 10(10), 2616; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10102616 - 01 Oct 2021
Cited by 13 | Viewed by 3085
Abstract
1,8-cineole, a monoterpenoid is a major component of eucalyptus oil and has been proven to possess numerous beneficial effects in humans. Notably, 1,8-cineole is the primary active ingredient of a clinically approved drug, Soledum® which is being mainly used for the maintenance [...] Read more.
1,8-cineole, a monoterpenoid is a major component of eucalyptus oil and has been proven to possess numerous beneficial effects in humans. Notably, 1,8-cineole is the primary active ingredient of a clinically approved drug, Soledum® which is being mainly used for the maintenance of sinus and respiratory health. Due to its clinically valuable properties, 1,8-cineole has gained significant scientific interest over the recent years specifically to investigate its anti-inflammatory and antioxidant effects. However, the impact of 1,8-cineole on the modulation of platelet activation, thrombosis and haemostasis was not fully established. Therefore, in this study, we demonstrate the effects of 1,8-cineole on agonists-induced platelet activation, thrombus formation under arterial flow conditions and haemostasis in mice. 1,8-cineole largely inhibits platelet activation stimulated by glycoprotein VI (GPVI) agonists such as collagen and cross-linked collagen-related peptide (CRP-XL), while it displays minimal inhibitory effects on thrombin or ADP-induced platelet aggregation. It inhibited inside-out signalling to integrin αIIbβ3 and outside-in signalling triggered by the same integrin as well as granule secretion and intracellular calcium mobilisation in platelets. 1,8-cineole affected thrombus formation on collagen-coated surface under arterial flow conditions and displayed a minimal effect on haemostasis of mice at a lower concentration of 6.25 µM. Notably, 1,8-cineole was found to be non-toxic to platelets up to 50 µM concentration. The investigation on the molecular mechanisms through which 1,8-cineole inhibits platelet function suggests that this compound affects signalling mediated by various molecules such as AKT, Syk, LAT, and cAMP in platelets. Based on these results, we conclude that 1,8-cineole may act as a potential therapeutic agent to control unwarranted platelet reactivity under various pathophysiological settings. Full article
(This article belongs to the Special Issue Research on Vascular Calcification in Cardiovascular Disease)
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13 pages, 1452 KiB  
Article
Development of the BioHybrid Assay: Combining Primary Human Vascular Smooth Muscle Cells and Blood to Measure Vascular Calcification Propensity
by Armand M. G. Jaminon, Asim C. Akbulut, Niko Rapp, Rafael Kramann, Erik A. L. Biessen, Lieve Temmerman, Barend Mees, Vincent Brandenburg, Robert Dzhanaev, Willi Jahnen-Dechent, Juergen Floege, Jouni Uitto, Chris P. Reutelingsperger and Leon J. Schurgers
Cells 2021, 10(8), 2097; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10082097 - 16 Aug 2021
Cited by 7 | Viewed by 2545
Abstract
Background: Vascular calcification is an active process that increases cardiovascular disease (CVD) risk. There is still no consensus on an appropriate biomarker for vascular calcification. We reasoned that the biomarker for vascular calcification is the collection of all blood components that can be [...] Read more.
Background: Vascular calcification is an active process that increases cardiovascular disease (CVD) risk. There is still no consensus on an appropriate biomarker for vascular calcification. We reasoned that the biomarker for vascular calcification is the collection of all blood components that can be sensed and integrated into a calcification response by human vascular smooth muscle cells (hVSMCs). Methods: We developed a new cell-based high-content assay, the BioHybrid assay, to measure in vitro calcification. The BioHybrid assay was compared with the o-Cresolphthalein assay and the T50 assay. Serum and plasma were derived from different cohort studies including chronic kidney disease (CKD) stages III, IV, V and VD (on dialysis), pseudoxanthoma elasticum (PXE) and other cardiovascular diseases including serum from participants with mild and extensive coronary artery calcification (CAC). hVSMCs were exposed to serum and plasma samples, and in vitro calcification was measured using AlexaFluor®-546 tagged fetuin-A as calcification sensor. Results: The BioHybrid assay measured the kinetics of calcification in contrast to the endpoint o-Cresolphthalein assay. The BioHybrid assay was more sensitive to pick up differences in calcification propensity than the T50 assay as determined by measuring control as well as pre- and post-dialysis serum samples of CKD patients. The BioHybrid response increased with CKD severity. Further, the BioHybrid assay discriminated between calcification propensity of individuals with a high CAC index and individuals with a low CAC index. Patients with PXE had an increased calcification response in the BioHybrid assay as compared to both spouse and control plasma samples. Finally, vitamin K1 supplementation showed lower in vitro calcification, reflecting changes in delta Agatston scores. Lower progression within the BioHybrid and on Agatston scores was accompanied by lower dephosphorylated-uncarboxylated matrix Gla protein levels. Conclusion: The BioHybrid assay is a novel approach to determine the vascular calcification propensity of an individual and thus may add to personalised risk assessment for CVD. Full article
(This article belongs to the Special Issue Research on Vascular Calcification in Cardiovascular Disease)
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11 pages, 698 KiB  
Article
Segmental Evaluation of Thoracic Aortic Calcium and Their Relations with Cardiovascular Risk Factors in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)
by Jesiana Ferreira Pedrosa, Luisa Campos Caldeira Brant, Stephanie Alves de Aquino, Antonio Luiz Ribeiro and Sandhi Maria Barreto
Cells 2021, 10(5), 1243; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10051243 - 18 May 2021
Cited by 5 | Viewed by 2263
Abstract
Thoracic aortic calcium (TAC) appears to be a subclinical marker of cardiovascular disease (CVD) and to predict cardiovascular (CV) mortality. However, studies on TAC use tomographic scans obtained for coronary artery calcium (CAC) score, which does not include the aortic arch. This study [...] Read more.
Thoracic aortic calcium (TAC) appears to be a subclinical marker of cardiovascular disease (CVD) and to predict cardiovascular (CV) mortality. However, studies on TAC use tomographic scans obtained for coronary artery calcium (CAC) score, which does not include the aortic arch. This study evaluates TAC prevalence in aortic arch (AAC), ascending (ATAC) and descending thoracic aorta (DTAC) and verify whether they are associated with the same CV risk factors. Cross-sectional analysis, including 2427 participants (mean age 55.6 ± 8.7; 54.1% women) of the ELSA-Brasil cohort. Nonenhanced ECG-gated tomographies were performed in 2015–2016. Multivariable logistic regression estimated the CV risk factors associated with calcium in each segment. Overall prevalence of ATAC, AAC and DTAC was, 23.1%, 62.1%, and 31.2%, respectively. About 90.4% of the individuals with TAC had AAC and only 19.5% had calcium in all segments. In the multivariable analysis, increasing age, lower levels of schooling, current smoking, higher body mass index, and hypertension remained associated with calcium in all segments. No sex or race/ethnicity differences were found in any aortic segment. Diabetes and dyslipidemia were associated with ATAC and DTAC, but not with AAC, suggesting that AAC may reflect an overlap of mechanisms that impact vascular health, including atherosclerosis. Full article
(This article belongs to the Special Issue Research on Vascular Calcification in Cardiovascular Disease)
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14 pages, 1036 KiB  
Article
Vascular Calcification Progression Modulates the Risk Associated with Vascular Calcification Burden in Incident to Dialysis Patients
by Antonio Bellasi, Luca Di Lullo, Domenico Russo, Roberto Ciarcia, Michele Magnocavallo, Carlo Lavalle, Carlo Ratti, Mario Cozzolino and Biagio Raffaele Di Iorio
Cells 2021, 10(5), 1091; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10051091 - 03 May 2021
Cited by 7 | Viewed by 2274
Abstract
Background: It is estimated that chronic kidney disease (CKD) accounts globally for 5 to 10 million deaths annually, mainly due to cardiovascular (CV) diseases. Traditional as well as non-traditional CV risk factors such as vascular calcification are believed to drive this disproportionate [...] Read more.
Background: It is estimated that chronic kidney disease (CKD) accounts globally for 5 to 10 million deaths annually, mainly due to cardiovascular (CV) diseases. Traditional as well as non-traditional CV risk factors such as vascular calcification are believed to drive this disproportionate risk burden. We aimed to investigate the association of coronary artery calcification (CAC) progression with all-cause mortality in patients new to hemodialysis (HD). Methods: Post hoc analysis of the Independent study (NCT00710788). At study inception and after 12 months of follow-up, 414 patients underwent computed tomography imaging for quantification of CAC via the Agatston methods. The square root method was used to assess CAC progression (CACP), and survival analyses were used to test its association with mortality. Results: Over a median follow-up of 36 months, 106 patients died from all causes. Expired patients were older, more likely to be diabetic or to have experienced an atherosclerotic CV event, and exhibited a significantly greater CAC burden (p = 0.002). Survival analyses confirmed an independent association of CAC burden (hazard ratio: 1.29; 95% confidence interval: 1.17–1.44) and CACP (HR: 5.16; 2.61–10.21) with all-cause mortality. CACP mitigated the risk associated with CAC burden (p = 0.002), and adjustment for calcium-free phosphate binder attenuated the strength of the link between CACP and mortality. Conclusions: CAC burden and CACP predict mortality in incident to dialysis patients. However, CACP reduced the risk associated with baseline CAC, and calcium-free phosphate binders attenuated the association of CACP and outcomes, suggesting that CACP modulation may improve survival in this population. Future endeavors are needed to confirm whether drugs or kidney transplantation may attenuate CACP and improve survival in HD patients. Full article
(This article belongs to the Special Issue Research on Vascular Calcification in Cardiovascular Disease)
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14 pages, 2274 KiB  
Article
Sodium [18F]Fluoride PET Can Efficiently Monitor In Vivo Atherosclerotic Plaque Calcification Progression and Treatment
by Alexandru Florea, Julius P. Sigl, Agnieszka Morgenroth, Andreas Vogg, Sabri Sahnoun, Oliver H. Winz, Jan Bucerius, Leon J. Schurgers and Felix M. Mottaghy
Cells 2021, 10(2), 275; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020275 - 30 Jan 2021
Cited by 11 | Viewed by 2532
Abstract
Given the high sensitivity and specificity of sodium [18F]Fluoride (Na[18F]F) for vascular calcifications and positive emerging data of vitamin K on vascular health, the aim of this study is to assess the ability of Na[18F]F to monitor [...] Read more.
Given the high sensitivity and specificity of sodium [18F]Fluoride (Na[18F]F) for vascular calcifications and positive emerging data of vitamin K on vascular health, the aim of this study is to assess the ability of Na[18F]F to monitor therapy and disease progression in a unitary atherosclerotic mouse model. ApoE−/− mice were placed on a Western-type diet for 12-weeks and then split into four groups. The early stage atherosclerosis group received a chow diet for an additional 12-weeks, while the advanced atherosclerosis group continued the Western-type diet. The Menaquinone-7 (MK-7) and Warfarin groups received MK-7 or Warfarin supplementation during the additional 12-weeks, respectively. Control wild type mice were fed a chow diet for 24-weeks. All of the mice were scanned with Na[18F]F using a small animal positron emission tomography (PET)/computed tomography (CT). The Warfarin group presented spotty calcifications on the CT in the proximal aorta. All of the spots corresponded to dense mineralisations on the von Kossa staining. After the control, the MK-7 group had the lowest Na[18F]F uptake. The advanced and Warfarin groups presented the highest uptake in the aortic arch and left ventricle. The advanced stage group did not develop spotty calcifications, however Na[18F]F uptake was still observed, suggesting the presence of micro-calcifications. In a newly applied mouse model, developing spotty calcifications on CT exclusively in the proximal aorta, Na[18F]F seems to efficiently monitor plaque progression and the beneficial effects of vitamin K on cardiovascular disease. Full article
(This article belongs to the Special Issue Research on Vascular Calcification in Cardiovascular Disease)
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13 pages, 2666 KiB  
Article
Infection of Porphyromonas gingivalis Increases Phosphate-Induced Calcification of Vascular Smooth Muscle Cells
by Hyun-Joo Park, Yeon Kim, Mi-Kyoung Kim, Hae-Ryoun Park, Hyung-Joon Kim, Soo-Kyung Bae and Moon-Kyoung Bae
Cells 2020, 9(12), 2694; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122694 - 15 Dec 2020
Cited by 8 | Viewed by 2256
Abstract
Accumulating evidence suggests a link between periodontal disease and cardiovascular diseases. Vascular calcification is the pathological precipitation of phosphate and calcium in the vasculature and is closely associated with increased cardiovascular risk and mortality. In this study, we have demonstrated that the infection [...] Read more.
Accumulating evidence suggests a link between periodontal disease and cardiovascular diseases. Vascular calcification is the pathological precipitation of phosphate and calcium in the vasculature and is closely associated with increased cardiovascular risk and mortality. In this study, we have demonstrated that the infection with Porphyromonas gingivalis (P. gingivalis), one of the major periodontal pathogens, increases inorganic phosphate-induced vascular calcification through the phenotype transition, apoptosis, and matrix vesicle release of vascular smooth muscle cells. Moreover, P. gingivalis infection accelerated the phosphate-induced calcium deposition in cultured rat aorta ex vivo. Taken together, our findings indicate that P. gingivalis contributes to the periodontal infection-related vascular diseases associated with vascular calcification. Full article
(This article belongs to the Special Issue Research on Vascular Calcification in Cardiovascular Disease)
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Review

Jump to: Research

19 pages, 1810 KiB  
Review
Myostatin/Activin-A Signaling in the Vessel Wall and Vascular Calcification
by Pasquale Esposito, Daniela Verzola, Daniela Picciotto, Leda Cipriani, Francesca Viazzi and Giacomo Garibotto
Cells 2021, 10(8), 2070; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10082070 - 12 Aug 2021
Cited by 5 | Viewed by 4066
Abstract
A current hypothesis is that transforming growth factor-β signaling ligands, such as activin-A and myostatin, play a role in vascular damage in atherosclerosis and chronic kidney disease (CKD). Myostatin and activin-A bind with different affinity the activin receptors (type I or II), activating [...] Read more.
A current hypothesis is that transforming growth factor-β signaling ligands, such as activin-A and myostatin, play a role in vascular damage in atherosclerosis and chronic kidney disease (CKD). Myostatin and activin-A bind with different affinity the activin receptors (type I or II), activating distinct intracellular signaling pathways and finally leading to modulation of gene expression. Myostatin and activin-A are expressed by different cell types and tissues, including muscle, kidney, reproductive system, immune cells, heart, and vessels, where they exert pleiotropic effects. In arterial vessels, experimental evidence indicates that myostatin may mostly promote vascular inflammation and premature aging, while activin-A is involved in the pathogenesis of vascular calcification and CKD-related mineral bone disorders. In this review, we discuss novel insights into the biology and physiology of the role played by myostatin and activin in the vascular wall, focusing on the experimental and clinical data, which suggest the involvement of these molecules in vascular remodeling and calcification processes. Moreover, we describe the strategies that have been used to modulate the activin downward signal. Understanding the role of myostatin/activin signaling in vascular disease and bone metabolism may provide novel therapeutic opportunities to improve the treatment of conditions still associated with high morbidity and mortality. Full article
(This article belongs to the Special Issue Research on Vascular Calcification in Cardiovascular Disease)
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14 pages, 2522 KiB  
Review
The Vascular Circadian Clock in Chronic Kidney Disease
by Søren Egstrand, Maria L. Mace, Klaus Olgaard and Ewa Lewin
Cells 2021, 10(7), 1769; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071769 - 13 Jul 2021
Cited by 5 | Viewed by 3216
Abstract
Chronic kidney disease is associated with extremely high cardiovascular mortality. The circadian rhythms (CR) have an impact on vascular function. The disruption of CR causes serious health problems and contributes to the development of cardiovascular diseases. Uremia may affect the master pacemaker of [...] Read more.
Chronic kidney disease is associated with extremely high cardiovascular mortality. The circadian rhythms (CR) have an impact on vascular function. The disruption of CR causes serious health problems and contributes to the development of cardiovascular diseases. Uremia may affect the master pacemaker of CR in the hypothalamus. A molecular circadian clock is also expressed in peripheral tissues, including the vasculature, where it regulates the different aspects of both vascular physiology and pathophysiology. Here, we address the impact of CKD on the intrinsic circadian clock in the vasculature. The expression of the core circadian clock genes in the aorta is disrupted in CKD. We propose a novel concept of the disruption of the circadian clock system in the vasculature of importance for the pathology of the uremic vasculopathy. Full article
(This article belongs to the Special Issue Research on Vascular Calcification in Cardiovascular Disease)
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27 pages, 939 KiB  
Review
Transthyretin: From Structural Stability to Osteoarticular and Cardiovascular Diseases
by Elżbieta Wieczorek and Andrzej Ożyhar
Cells 2021, 10(7), 1768; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071768 - 13 Jul 2021
Cited by 19 | Viewed by 4252
Abstract
Transthyretin (TTR) is a tetrameric protein transporting hormones in the plasma and brain, which has many other activities that have not been fully acknowledged. TTR is a positive indicator of nutrition status and is negatively correlated with inflammation. TTR is a neuroprotective and [...] Read more.
Transthyretin (TTR) is a tetrameric protein transporting hormones in the plasma and brain, which has many other activities that have not been fully acknowledged. TTR is a positive indicator of nutrition status and is negatively correlated with inflammation. TTR is a neuroprotective and oxidative-stress-suppressing factor. The TTR structure is destabilized by mutations, oxidative modifications, aging, proteolysis, and metal cations, including Ca2+. Destabilized TTR molecules form amyloid deposits, resulting in senile and familial amyloidopathies. This review links structural stability of TTR with the environmental factors, particularly oxidative stress and Ca2+, and the processes involved in the pathogenesis of TTR-related diseases. The roles of TTR in biomineralization, calcification, and osteoarticular and cardiovascular diseases are broadly discussed. The association of TTR-related diseases and vascular and ligament tissue calcification with TTR levels and TTR structure is presented. It is indicated that unaggregated TTR and TTR amyloid are bound by vicious cycles, and that TTR may have an as yet undetermined role(s) at the crossroads of calcification, blood coagulation, and immune response. Full article
(This article belongs to the Special Issue Research on Vascular Calcification in Cardiovascular Disease)
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14 pages, 1122 KiB  
Review
The Effects of Warfarin and Direct Oral Anticoagulants on Systemic Vascular Calcification: A Review
by Kalaimani Elango, Awad Javaid, Banveet K. Khetarpal, Sathishkumar Ramalingam, Krishna Prasad Kolandaivel, Kulothungan Gunasekaran and Chowdhury Ahsan
Cells 2021, 10(4), 773; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10040773 - 31 Mar 2021
Cited by 23 | Viewed by 8657
Abstract
Warfarin has been utilized for decades as an effective anticoagulant in patients with a history of strong risk factors for venous thromboembolism (VTE). Established adverse effects include bleeding, skin necrosis, teratogenicity during pregnancy, cholesterol embolization, and nephropathy. One of the lesser-known long-term side [...] Read more.
Warfarin has been utilized for decades as an effective anticoagulant in patients with a history of strong risk factors for venous thromboembolism (VTE). Established adverse effects include bleeding, skin necrosis, teratogenicity during pregnancy, cholesterol embolization, and nephropathy. One of the lesser-known long-term side effects of warfarin is an increase in systemic arterial calcification. This is significant due to the association between vascular calcification and cardiovascular morbidity and mortality. Direct oral anticoagulants (DOACs) have gained prominence in recent years, as they require less frequent monitoring and have a superior side effect profile to warfarin, specifically in relation to major bleeding. The cost and lack of data for DOACs in some disease processes have precluded universal use. Within the last four years, retrospective cohort studies, observational studies, and randomized trials have shown, through different imaging modalities, that multiple DOACs are associated with slower progression of vascular calcification than warfarin. This review highlights the pathophysiology and mechanisms behind vascular calcification due to warfarin and compares the effect of warfarin and DOACs on systemic vasculature. Full article
(This article belongs to the Special Issue Research on Vascular Calcification in Cardiovascular Disease)
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22 pages, 1845 KiB  
Review
Uremic Toxins Affecting Cardiovascular Calcification: A Systematic Review
by Jana Holmar, Sofia de la Puente-Secades, Jürgen Floege, Heidi Noels, Joachim Jankowski and Setareh Orth-Alampour
Cells 2020, 9(11), 2428; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9112428 - 06 Nov 2020
Cited by 12 | Viewed by 2709
Abstract
Cardiovascular calcification is highly prevalent and associated with increased morbidity in chronic kidney disease (CKD). This review examines the impact of uremic toxins, which accumulate in CKD due to a failing kidney function, on cardiovascular calcification. A systematic literature search identified 41 uremic [...] Read more.
Cardiovascular calcification is highly prevalent and associated with increased morbidity in chronic kidney disease (CKD). This review examines the impact of uremic toxins, which accumulate in CKD due to a failing kidney function, on cardiovascular calcification. A systematic literature search identified 41 uremic toxins that have been studied in relation to cardiovascular calcification. For 29 substances, a potentially causal role in cardiovascular calcification was addressed in in vitro or animal studies. A calcification-inducing effect was revealed for 16 substances, whereas for three uremic toxins, namely the guanidino compounds asymmetric and symmetric dimethylarginine, as well as guanidinosuccinic acid, a calcification inhibitory effect was identified in vitro. At a mechanistic level, effects of uremic toxins on calcification could be linked to the induction of inflammation or oxidative stress, smooth muscle cell osteogenic transdifferentiation and/or apoptosis, or alkaline phosphatase activity. For all middle molecular weight and protein-bound uremic toxins that were found to affect cardiovascular calcification, an increasing effect on calcification was revealed, supporting the need to focus on an increased removal efficiency of these uremic toxin classes in dialysis. In conclusion, of all uremic toxins studied with respect to calcification regulatory effects to date, more uremic toxins promote rather than reduce cardiovascular calcification processes. Additionally, it highlights that only a relatively small part of uremic toxins has been screened for effects on calcification, supporting further investigation of uremic toxins, as well as of associated post-translational modifications, on cardiovascular calcification processes. Full article
(This article belongs to the Special Issue Research on Vascular Calcification in Cardiovascular Disease)
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