Pathophysiological Role of Vascular Smooth Muscle Alkaline Phosphatase in Medial Artery Calcification

Sheen, Campbell R.; Kuss, Pia; Narisawa, Sonoko; Yadav, Manisha; Nigro, Jessica; Wang, Wei; Chhea, Thangchanthida; Sergienko, Eduard; Kapoor, Kapil; Jackson, Michael R.; Hoylaerts, Marc; Pinkerton, Anthony B.; O’Neill, W. Charles; Millán, José Luis

doi:10.1002/jbmr.2420

Cited by 170 publications

(216 citation statements)

References 59 publications

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“…Furthermore, vascular NF-κB promotes expression of CBFA1, which also increases ALPL expression and is required for phosphate-induced vascular calcification (37)(38)(39). ALPL degrades PPi, an inhibitor of hydroxyapatite formation and mineral deposition in the vascular tissue (8). ALPL overexpression is sufficient to cause generalized vascular calcification and has emerged as a key enzyme in vascular calcification (40).…”

Section: Methodsmentioning

confidence: 99%

“…ALPL overexpression is sufficient to cause generalized vascular calcification and has emerged as a key enzyme in vascular calcification (40). A downstream product of NF-κB activation is TTP (41), an RNA-destabilizing factor that inhibits ANKH expression and, thus, the export of PPi in the extracellular space (8,28). SGK1-induced decrease in PPi levels may result from both enhanced ALPL activity and reduced ANKH expression.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, the transformed VSMCs express tissue-nonspecific ALPL (alkaline phosphatase, liver/bone/kidney), which cleaves the powerful calcification inhibitor pyrophosphate (PPi) (8). The upregulation of alkaline phosphatase is, therefore, a critical event leading to mineral deposition in vascular calcification (8).…”

Section: Introductionmentioning

confidence: 99%

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SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling

Voelkl

Luong

Tuffaha

et al. 2018

Journal of Clinical Investigation

133

142

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling

Voelkl

Luong

Tuffaha

et al. 2018

Journal of Clinical Investigation

133

142

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“…Higher ALP levels are correlated with increased risk of cardiovascular disease, calcification, and mortality in populations with and without CKD [14-16]. Pharmacological inhibition of ALP improves vascular calcification, cardiac hypertrophy and survival in an animal model of vascular ALP overexpression [17]. Serum ALP has also been associated with CKD progression and proteinuria [13, 18].…”

Section: Introductionmentioning

confidence: 99%

Apabetalone Mediated Epigenetic Modulation is Associated with Favorable Kidney Function and Alkaline Phosphatase Profile in Patients with Chronic Kidney Disease

Kulikowski

Halliday

Johansson³

et al. 2018

Kidney Blood Press Res

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Background/Aims: The association between serum alkaline phosphatase (ALP) with adverse cardiovascular outcomes, in Chronic Kidney Disease (CKD) patients has previously been reported and may be a result of increased vascular calcification and inflammation. Here we report, for the first time, the effects of pharmacologic epigenetic modulation on levels of ALP and kidney function via a novel oral small molecule BET inhibitor, apabetalone, in CKD patients. Methods: A post-hoc analysis evaluated patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m², who participated in the apabetalone phase 2 randomized controlled trials (SUSTAIN and ASSURE). 48 CKD subjects with a history of cardiovascular disease (CVD) were treated with 100mg twice-daily of 24 and 26 weeks of apabetalone or placebo. ALP and eGFR were measured prior to randomization and at final visits. Results: Patients who received apabetalone (n=35) versus placebo (n=13) over 6 months showed significantly (p=0.02) lowered serum ALP -14.0% (p<0.0001 versus baseline) versus -6.3% (p=0.9 versus baseline). The eGFR in the apabetalone group increased by 3.4% (1.7 mL/min/1.73 m²) (p=0.04 versus baseline) and decreased by 5.8% (2.9 mL/min/1.73 m²) (p=0.6 versus baseline) in the placebo group. Apabetalone was well tolerated. Conclusion: A post-hoc analysis of CKD subjects from the SUSTAIN and ASSURE randomized controlled trials demonstrated favorable effects of apabetalone on ALP and eGFR, and generated the hypothesis that epigenetic modulation by BET inhibition may potentially offer a novel therapeutic strategy to treat CVD and progressive kidney function loss in CKD patients. This is being examined in the phase III trial BETonMACE.

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“…Oxidative stress is an important mediator of osteo-/chondrogenic transdifferentiation of VSMCs [28-30]. These transdifferentiated VSMCs express osteogenic and chondrogenic transcription factors, such as msh homeobox 2 (MSX2), core-binding factor α-1 (CBFA1) and SRY-Box 9 (SOX9) [24, 31, 32], as well as osteogenic enzymes, such as tissue non-specific alkaline phosphatase (ALPL) [33] to cause an active mineralization of vascular tissue.…”

Section: Introductionmentioning

confidence: 99%

Fibulin-3 Attenuates Phosphate-Induced Vascular Smooth Muscle Cell Calcification by Inhibition of Oxidative Stress

Luong

Schelski

Boehme

et al. 2018

Cell Physiol Biochem

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Background/Aims: Fibulin-3, an extracellular matrix glycoprotein, inhibits vascular oxidative stress and remodeling in hypertension. Oxidative stress is prevalent in chronic kidney disease (CKD) patients and is an important mediator of osteo-/chondrogenic transdifferentiation and calcification of vascular smooth muscle cells (VSMCs) during hyperphosphatemia. Therefore, the present study explored the effects of Fibulin-3 on phosphate-induced vascular calcification. Methods: Experiments were performed in primary human aortic smooth muscle cells (HAoSMCs) treated with control or with phosphate without or with additional treatment with recombinant human Fibulin-3 protein or with hydrogen peroxide as an exogenous source of oxidative stress. Results: Treatment with calcification medium significantly increased calcium deposition in HAoSMCs, an effect significantly blunted by additional treatment with Fibulin-3. Moreover, phosphate-induced alkaline phosphatase activity and mRNA expression of osteogenic and chondrogenic markers MSX2, CBFA1, SOX9 and ALPL were all significantly reduced by addition of Fibulin-3. These effects were paralleled by similar regulation of oxidative stress in HAoSMCs. Phosphate treatment significantly up-regulated mRNA expression of the oxidative stress markers NOX4 and CYBA, down-regulated total antioxidant capacity and increased the expression of downstream effectors of oxidative stress PAI-1, MMP2 and MMP9 as well as BAX/BLC2 ratio in HAoSMCs, all effects blocked by additional treatment with Fibulin-3. Furthermore, the protective effects of Fibulin-3 on phosphate-induced osteogenic and chondrogenic markers expression in HAoSMCs were reversed by additional treatment with hydrogen peroxide. Conclusions: Fibulin-3 attenuates phosphate-induced osteo-/ chondrogenic transdifferentiation and calcification of VSMCs, effects involving inhibition of oxidative stress. Up-regulation or supplementation of Fibulin-3 may be beneficial in reducing the progression of vascular calcification during hyperphosphatemic conditions such as CKD.

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Pathophysiological Role of Vascular Smooth Muscle Alkaline Phosphatase in Medial Artery Calcification

Cited by 170 publications

References 59 publications

SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling

SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling

Apabetalone Mediated Epigenetic Modulation is Associated with Favorable Kidney Function and Alkaline Phosphatase Profile in Patients with Chronic Kidney Disease

Fibulin-3 Attenuates Phosphate-Induced Vascular Smooth Muscle Cell Calcification by Inhibition of Oxidative Stress

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