Development, establishment and validation of in vitro and ex vivo assays of vascular calcification

Holmar, Jana; Noels, Heidi; Böhm, Michael; Bhargava, Shruti; Jankowski, Joachim; Orth-Alampour, Setareh

doi:10.1016/j.bbrc.2020.05.085

Cited by 16 publications

(15 citation statements)

References 20 publications

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“…1 b). Each resultant fraction was tested for its inhibitory effect on vascular calcification using the ex vivo thoracic aortic ring calcification assay [ 31 ], and fractions with inhibitory activity were then further fractionated by anion-exchange chromatography (Fig. 1 c).…”

Section: Resultsmentioning

confidence: 99%

“…1 d). The resulting fractions were again tested for their inhibitory effects on vascular calcification via thoracic aortic ring calcification assay as recently described [ 31 ]. Fractions showing strong inhibitory effects (indicated by the arrow in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The thoracic region of the aorta of Wistar rats was used to analyse the effect of chromatographic fractions on calcification, since this region of the aorta shows a reproducible degree of calcification [ 31 ]. The thoracic aortic rings were incubated with a non-calcifying medium (NCM) and calcifying medium (CM) in the presence of adrenal gland chromatographic fractions for 7 days.…”

Section: Methodsmentioning

confidence: 99%

“…The thoracic region of the aorta of Wistar rats was used to analyse the effect of the identified peptides on calcification, since this region of the aorta shows a reproducible degree of calcification [ 31 ]. The endothelial layer of each thoracic aortic ring was manually damaged.…”

Section: Methodsmentioning

confidence: 99%

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Prevention of vascular calcification by the endogenous chromogranin A-derived mediator that inhibits osteogenic transdifferentiation

et al. 2021

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The adrenal glands participate in cardiovascular (CV) physiology and the pathophysiology of CV diseases through their effects on sodium and water metabolism, vascular tone and cardiac function. In the present study, we identified a new adrenal compound controlling mesenchymal cell differentiation that regulates osteoblastic differentiation in the context of vascular calcification. This peptide was named the “calcification blocking factor” (CBF) due to its protective effect against vascular calcification and is released from chromogranin A via enzymatic cleavage by calpain 1 and kallikrein. CBF reduced the calcium content of cells and thoracic aortic rings under calcifying culture conditions, as well as in aortas from animals treated with vitamin D and nicotine (VDN animals). Furthermore, CBF prevented vascular smooth muscle cell (VSMC) transdifferentiation into osteoblast-like cells within the vascular wall via the sodium-dependent phosphate transporter PIT-1 and by inhibition of NF-κB activation and the subsequent BMP2/p-SMAD pathway. Pulse pressure, a marker of arterial stiffness, was significantly decreased in VDN animals treated with CBF. In line with our preclinical data, CBF concentration is significantly reduced in diseases characterized by increased calcification, as shown in patients with chronic kidney disease. In preparation for clinical translation, the active site of the native 19-AS long native CBF was identified as EGQEEEED. In conclusion, we have identified the new peptide CBF, which is secreted from the adrenal glands and might prevent vascular calcification by inhibition of osteogenic transdifferentiation. The anti-calcific effects of CBF and short active site may therefore promote the development of new tools for the prevention and/or treatment of vascular calcification.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Prevention of vascular calcification by the endogenous chromogranin A-derived mediator that inhibits osteogenic transdifferentiation

et al. 2021

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“…Additionally, studying combinatorial and/or synergistic effects of uremic toxins are of importance as well, since previous studies revealed that combining blood levels of low molecular weight uremic toxins may help to improve the estimated survival of CKD stage 5D patients [85]. Preferentially, this should be done by a systematic approach, using standardized models for analyzing cardiovascular calcification in vitro and ex vivo [86].…”

Section: Discussionmentioning

confidence: 99%

Uremic Toxins Affecting Cardiovascular Calcification: A Systematic Review

Holmar

Puente-Secades

Floege

et al. 2020

Cells

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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.

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Flavocoxid Ameliorates Aortic Calcification Induced by Hypervitaminosis D3 and Nicotine in Rats Via Targeting TNF-α, IL-1β, iNOS, and Osteogenic Runx2

Amer

Shehatou

El‐Kashef

et al. 2021

Cardiovasc Drugs Ther

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Development, establishment and validation of in vitro and ex vivo assays of vascular calcification

Cited by 16 publications

References 20 publications

Prevention of vascular calcification by the endogenous chromogranin A-derived mediator that inhibits osteogenic transdifferentiation

Prevention of vascular calcification by the endogenous chromogranin A-derived mediator that inhibits osteogenic transdifferentiation

Uremic Toxins Affecting Cardiovascular Calcification: A Systematic Review

Flavocoxid Ameliorates Aortic Calcification Induced by Hypervitaminosis D3 and Nicotine in Rats Via Targeting TNF-α, IL-1β, iNOS, and Osteogenic Runx2

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