A protective role for FGF-23 in local defence against disrupted arterial wall integrity?

Zhu, Dongxing; Mackenzie, Neil E.; Millán, José Luis; Farquharson, Colin; MacRae, Vicky

doi:10.1016/j.mce.2013.03.008

Cited by 60 publications

(69 citation statements)

References 53 publications

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“…medium (Invitrogen) for 20 mins. After 24 h, cells were cultured in control or high inorganic phosphate (P i ) medium (α-minimal essential medium supplemented with 10% fetal calf serum, 1% gentamycin and 2 mM Na 2 HPO 4 /NaH 2 PO 4 pH7.4), which we have previously shown to induce calcification after 7 days in culture 11. At day 3 in high P i medium, the medium was changed and a repeat transfection mix was added to the fresh medium.…”

Section: Methodsmentioning

confidence: 99%

miRNA‐221 and miRNA‐222 synergistically function to promote vascular calcification

Mackenzie

Staines

Zhu

et al. 2013

Cell Biochemistry & Function

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Vascular calcification shares many similarities with skeletal mineralisation and involves the phenotypic trans-differentiation of vascular smooth muscle cells (VSMCs) to osteoblastic cells within a calcified environment. Various microRNAs (miRs) are known to regulate cell differentiation; however, their role in mediating VSMC calcification is not fully understood. miR-microarray analysis revealed the significant down-regulation of a range of miRs following nine days in culture, including miR-199b, miR-29a, miR-221, miR-222 and miR-31 (p < 0.05). Subsequent studies investigated the specific role of the miR-221/222 family in VSMC calcification. Real-time quantitative polymerase chain reaction data confirmed the down-regulation of miR-221 (32.4%; p < 0.01) and miR-222 (15.7%; p < 0.05). VSMCs were transfected with mimics of miR-221 and miR-222, individually and in combination. Increased calcium deposition was observed in the combined treatment (two-fold; p < 0.05) but not in individual treatments. Runx2 and Msx2 expression was increased during calcification, but no difference in expression was observed following transfection with miR mimics. Interestingly, miR-221 and miR-222 mimics induced significant changes in ectonucleotide phosphodiesterase 1 (Enpp1) and Pit-1 expression, suggesting that these miRs may modulate VSMC calcification through cellular inorganic phosphate and pyrophosphate levels. © 2013 The Authors. Cell Biochemistry and Function published by John Wiley & Sons, Ltd.

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Section: Methodsmentioning

confidence: 99%

miRNA‐221 and miRNA‐222 synergistically function to promote vascular calcification

Mackenzie

Staines

Zhu

et al. 2013

Cell Biochemistry & Function

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“…Due to its role in mineralization, FGF23 was clinically associated with vascular calcification (13,14,31,48,52,62). However, most recently it has been shown that FGF23 does not promote (42,54), but may actually prevent, vascular calcification (76). Nevertheless, FGF23 may have other effects on the vasculature.…”

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confidence: 99%

FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability

Silswal

Touchberry

Daniel

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

151

102

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MJ. FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability. Am J Physiol Endocrinol Metab 307: E426 -E436, 2014. First published July 15, 2014 doi:10.1152/ajpendo.00264.2014.-Fibroblast growth factor 23 (FGF23) is secreted primarily by osteocytes and regulates phosphate and vitamin D metabolism. Elevated levels of FGF23 are clinically associated with endothelial dysfunction and arterial stiffness in chronic kidney disease (CKD) patients; however, the direct effects of FGF23 on endothelial function are unknown. We hypothesized that FGF23 directly impairs endothelial vasorelaxation by hindering nitric oxide (NO) bioavailability. We detected expression of all four subtypes of FGF receptors (Fgfr1-4) in male mouse aortas. Exogenous FGF23 (90 -9,000 pg/ml) did not induce contraction of aortic rings and did not relax rings precontracted with PGF 2␣. However, preincubation with FGF23 (9,000 pg/ml) caused a ϳ36% inhibition of endothelium-dependent relaxation elicited by acetylcholine (ACh) in precontracted aortic rings, which was prevented by the FGFR antagonist PD166866 (50 nM). Furthermore, in FGF23-pretreated (9,000 pg/ml) aortic rings, we found reductions in NO levels. We also investigated an animal model of CKD (Col4a3 Ϫ/Ϫ mice) that displays highly elevated serum FGF23 levels and found they had impaired endothelium-dependent vascular relaxation and reduced nitrate production compared with age-matched wild types. To elucidate a mechanism for the FGF23-induced impairment, we measured superoxide levels in endothelial cells and aortic rings and found that they were increased following FGF23 treatment. Crucially, treatment with the superoxide scavenger tiron reduced superoxide levels and also restored aortic relaxation to ACh. Therefore, our data suggest that FGF23 increases superoxide, inhibits NO bioavailability, and causes endothelial dysfunction in mouse aorta. Together, these data provide evidence that high levels of FGF23 contribute to cardiovascular dysfunction. fibroblast growth factor 23; chronic kidney disease; nitric oxide; superoxide; and cardiovascular disease IT IS WELL KNOWN THAT PATIENTS with chronic kidney disease (CKD) have an increased risk of cardiovascular disease (CVD). Modification of the traditional risk factors for CVD (e.g., dyslipidemia, hypertension, anemia, and hyperhomocysteinemia) does not improve cardiovascular function in patients with CKD (32), suggesting that other factors may be responsible. Fibroblast growth factor 23 (FGF23) is a hormone secreted by osteocytes that serves as an important regulator of serum phosphate and vitamin D via direct actions on the kidney and parathyroid (6,8). Recently, high circulating levels of FGF23 have been clinically associated with the development of CVD (3,9,33,47,55,72) especially during CKD where serum FGF23 is substantially increased 10-to 1,000-fold (30, 37). Nevertheless, despite these clinical associations, there have been relatively few studies to determine whethe...

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“…Irrespective of phosphorous levels, FGF-23 independently predicts survival chances of chronic HD patients [28,29]. However, whether FGF-23 plays an active pathogenetic role in uremic vascular calcification remains uncertain, and experimental studies have exhibited opposing effects on the calcification process [30,31]. Recently, there is growing evidence of the role of the Wnt-ß-catenin signaling pathway in vascular calcification.…”

Section: Discussionmentioning

confidence: 99%

Association Between Risk Factors Including Bone-Derived Biomarkers and Aortic Arch Calcification in Maintenance Hemodialysis Patients

Nitta

Hanafusa

Okazaki

et al. 2018

Kidney Blood Press Res

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Background/Aims: Aortic arch calcification (AoAC) is frequently detected in maintenance hemodialysis (MHD) patients and is associated with cardiovascular and all-cause mortality. We investigated the factors associated with AoAC and analyzed the relationship between the factors including bone-derived biomarkers and AoAC. Methods: We enrolled 389 stable MHD patients. AoAC was assessed using chest-X ray examination. Demographic data was collected in addition to serum levels of biochemical and bone-derived biomarkers, including sclerostin and fibroblast growth factor-23 (FGF-23). Results: Two hundred sixteen patients (55.5%) had AoAC. Patients with AoAC score ≥ 4 were older, with a higher percentage being male, and exhibited lower serum levels of albumin and triglyceride. Serum FGF-23 levels were inversely associated with AoAC severity, and FGF-23was directly related to vascular calcification. Age, gender, and dialysis vintage were independent predictors of AoAC. Conclusion: MHD patients have a high prevalence of AoAC. The grade of AoAC was dependent on older age in association with longer dialysis vintage. Levels of circulating FGF-23 but not sclerostin were related to AoAC severity. Serum FGF-23 levels were independently associated with AoAC.

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A protective role for FGF-23 in local defence against disrupted arterial wall integrity?

Cited by 60 publications

References 53 publications

miRNA‐221 and miRNA‐222 synergistically function to promote vascular calcification

miRNA‐221 and miRNA‐222 synergistically function to promote vascular calcification

FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability

Association Between Risk Factors Including Bone-Derived Biomarkers and Aortic Arch Calcification in Maintenance Hemodialysis Patients

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