The biology of vascular calcification

Quaglino, Daniela; Boraldi, Federica; Lofaro, Francesco Demetrio

doi:10.1016/bs.ircmb.2020.02.007

Cited by 40 publications

(25 citation statements)

References 508 publications

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“…All patients exhibited a similar clinical phenotype characterized by lax and redundant skin and by ocular bleeding and choroidal neovascularization. Patient #1 was compound heterozygous for a stop codon mutation (c.3421C > T; p.Arg1141 * ) and for a large deletion in exon 23_29 (c.2996_4208del p.Ala999_Ser1403del); patient #2 was compound heterozygous for two stop codon mutations (c.1552C > T, p.Arg518 * and c.3088c > T, p.Arg1030 * ); and patient #3 was compound heterozygous for a missense mutation (c.4198G > A, p.Glu1400Lys) and for a deletion in exon 23_29 (c.2996_4208del p.Ala999_Ser1403del) (Quaglino et al, 2011(Quaglino et al, , 2020. The fibroblasts were cultured, as already described with some modification (Quaglino et al, 2000), using Dulbecco's Modified Eagle Medium (DMEM; Gibco, Grand Island, NY, United States) supplemented with 10% fetal bovine serum and non-essential amino acids 1 × (Gibco), but without penicillin and streptomycin because antibiotics may interfere with mitochondrial respiration and reactive oxygen species (ROS) production.…”

Section: Cell Culturesmentioning

confidence: 99%

“…The clinical phenotype reminds of premature aging syndrome (Tiemann et al, 2020), being characterized by multisystem clinical manifestations due to progressive calcification of skin, eyes, and the cardiovascular system (Quaglino et al, 2011;Murro et al, 2018;Murro et al, 2019). The pathomechanisms of PXE, as well as the complex pathways responsible for hydroxyapatite deposition in soft connective tissues, are still under investigation (Quaglino et al, 2011(Quaglino et al, , 2020.…”

Section: Introductionmentioning

confidence: 99%

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Relationship Between Mitochondrial Structure and Bioenergetics in Pseudoxanthoma elasticum Dermal Fibroblasts

Lofaro

Boraldi

García-Fernández

et al. 2020

Front. Cell Dev. Biol.

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Pseudoxanthoma elasticum (PXE) is a genetic disease considered as a paradigm of ectopic mineralization disorders, being characterized by multisystem clinical manifestations due to progressive calcification of skin, eyes, and the cardiovascular system, resembling an age-related phenotype. Although fibroblasts do not express the pathogenic ABCC6 gene, nevertheless these cells are still under investigation because they regulate connective tissue homeostasis, generating the “arena” where cells and extracellular matrix components can promote pathologic calcification and where activation of pro-osteogenic factors can be associated to pathways involving mitochondrial metabolism. The aim of the present study was to integrate structural and bioenergenetic features to deeply investigate mitochondria from control and from PXE fibroblasts cultured in standard conditions and to explore the role of mitochondria in the development of the PXE fibroblasts’ pathologic phenotype. Proteomic, biochemical, and morphological data provide new evidence that in basal culture conditions (1) the protein profile of PXE mitochondria reveals a number of differentially expressed proteins, suggesting changes in redox balance, oxidative phosphorylation, and calcium homeostasis in addition to modified structure and organization, (2) measure of oxygen consumption indicates that the PXE mitochondria have a low ability to cope with a sudden increased need for ATP via oxidative phosphorylation, (3) mitochondrial membranes are highly polarized in PXE fibroblasts, and this condition contributes to increased reactive oxygen species levels, (4) ultrastructural alterations in PXE mitochondria are associated with functional changes, and (5) PXE fibroblasts exhibit a more abundant, branched, and interconnected mitochondrial network compared to control cells, indicating that fusion prevail over fission events. In summary, the present study demonstrates that mitochondria are modified in PXE fibroblasts. Since mitochondria are key players in the development of the aging process, fibroblasts cultured from aged individuals or aged in vitro are more prone to calcify, and in PXE, calcified tissues remind features of premature aging syndromes; it can be hypothesized that mitochondria represent a common link contributing to the development of ectopic calcification in aging and in diseases. Therefore, ameliorating mitochondrial functions and cell metabolism could open new strategies to positively regulate a number of signaling pathways associated to pathologic calcification.

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Section: Cell Culturesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Relationship Between Mitochondrial Structure and Bioenergetics in Pseudoxanthoma elasticum Dermal Fibroblasts

Lofaro

Boraldi

García-Fernández

et al. 2020

Front. Cell Dev. Biol.

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“…aldosterone partly regulates Na + and K + homeostasis by modulating Na + resorption in kidney. However, the renin-angiotensinaldosterone system (RAAS) has additional physiological effects in increasing vascular wall stiff, causing cardiomyocyte hypertrophy, and modulating cell proliferation [6][7][8]. Additionally, aldosterone plays a key role in the pathophysiology of hypertension, chronic heart failure [9], myocar-dial infarction remodeling [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Aldosterone is a possible new stimulating factor for promoting vascular calcification

Zhang

Zhou

Huang

et al. 2021

Front. Biosci. (Landmark Ed)

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Introduction 3. Methods 3.1 Animal model preparation 3.2 Experiments 3.3 Data analysis 4. Results 4.1 Noninvasive blood pressure, weight loss, and cardiac weight index of rats 4.2 Von Kossa staining in the aorta 4.3 The calcium content and the activity of ALP in the aorta tissue 4.4 Masson's trichrome staining 4.5 The content of the C-reactive protein, IL-6, TNF-α and MCP-1 in serum 4.6 The content of Urotensin II and aldosterone in the aorta tissue 4.7 The change of the immunoreactivity 5. Discussion 6. Conclusions 7. Author contributions 8. Ethics approval and consent to participate 9. Acknowledgment 10. Funding 11. Conflict of interest 12. Availability of data and materials 13. References

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“…To date, information on soft connective tissue mineralization comes from studies mainly performed on vascular calcification [14], where it has been demonstrated that cells undergo osteogenic differentiation due to activation of different signalling pathways (i.e., TGF-β signalling, BMPs-Smad-Runx2 signalling, Wnt-Msx2 signalling) [15]. Very recently, the role of TGF-β/BMP signalling has been confirmed in a number of patients with dermal ectopic calcification [13].…”

Section: Introductionmentioning

confidence: 99%

Dermal Alterations in Clinically Unaffected Skin of Pseudoxanthoma elasticum Patients

Boraldi

Lofaro

Losi

et al. 2021

JCM

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Background: Pseudoxanthoma elasticum (PXE), due to rare sequence variants in the ABCC6 gene, is characterized by calcification of elastic fibers in several tissues/organs; however, the pathomechanisms have not been completely clarified. Although it is a systemic disorder on a genetic basis, it is not known why not all elastic fibers are calcified in the same patient and even in the same tissue. At present, data on soft connective tissue mineralization derive from studies performed on vascular tissues and/or on clinically affected skin, but there is no information on patients’ clinically unaffected skin. Methods: Skin biopsies from clinically unaffected and affected areas of the same PXE patient (n = 6) and from healthy subjects were investigated by electron microscopy. Immunohistochemistry was performed to evaluate p-SMAD 1/5/8 and p-SMAD 2/3 expression and localization. Results: In clinically unaffected skin, fragmented elastic fibers were prevalent, whereas calcified fibers were only rarely observed at the ultrastructural level. p-SMAD1/5/8 and p-SMAD2/3 were activated in both affected and unaffected skin. Conclusion: These findings further support the concept that fragmentation/degradation is necessary but not sufficient to cause calcification of elastic fibers and that additional local factors (e.g., matrix composition, mechanical forces and mesenchymal cells) contribute to create the pro-osteogenic environment.

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The biology of vascular calcification

Cited by 40 publications

References 508 publications

Relationship Between Mitochondrial Structure and Bioenergetics in Pseudoxanthoma elasticum Dermal Fibroblasts

Relationship Between Mitochondrial Structure and Bioenergetics in Pseudoxanthoma elasticum Dermal Fibroblasts

Aldosterone is a possible new stimulating factor for promoting vascular calcification

Dermal Alterations in Clinically Unaffected Skin of Pseudoxanthoma elasticum Patients

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