Extracellular pyrophosphate metabolism and calcification in vascular smooth muscle

Extracellular inorganic pyrophosphate (ePPi) is an important endogenous inhibitor of vascular calcification, but it is not known whether systemic or local vascular PPi metabolism controls calcification. To determine the role of ePPi in vascular smooth muscle, we identified the pathways responsible for ePPi production and hydrolysis in rat and mouse aortas and manipulated them to demonstrate their role in the calcification of isolated aortas in culture. Rat and mouse aortas contained mRNA for ectonucleotide pyrophosphatase/phosphodiesterases (NPP1–3), the putative PPi transporter ANK, and tissue-nonspecific alkaline phosphatase (TNAP). Synthesis of PPi from ATP in aortas was blocked by β,γ-methylene-ATP, an inhibitor of NPPs. Aortas from mice lacking NPP1 ( Enpp1−/−) did not synthesize PPi from ATP and exhibited increased calcification in culture. Although ANK-mediated transport of PPi could not be demonstrated in aortas, aortas from mutant ( ank/ank) mice calcified more in culture than did aortas from normal (ANK/ANK) mice. Hydrolysis of PPi was reduced 25% by β,γ-methylene-ATP and 50% by inhibition of TNAP. Hydrolysis of PPi was increased in cells overexpressing TNAP or NPP3 but not NPP1 and was not reduced in Enpp1−/− aortas. Overexpression of TNAP increased calcification of cultured aortas. The results show that smooth muscle NPP1 and TNAP control vascular calcification through effects on synthesis and hydrolysis of ePPi, indicating an important inhibitory role of locally produced PPi. Smooth muscle ANK also affects calcification, but this may not be mediated through transport of PPi. NPP3 is identified as an additional pyrophosphatase that could influence vascular calcification.

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

Journal of Bone and Mineral Research ◽

10.1002/jbmr.2420 ◽

2015 ◽

Vol 30 (5) ◽

pp. 824-836 ◽

Cited By ~ 102

Author(s):

Campbell R Sheen ◽

Pia Kuss ◽

Sonoko Narisawa ◽

Manisha C Yadav ◽

Jessica Nigro ◽

...

Keyword(s):

Alkaline Phosphatase ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Pathophysiological Role ◽

Medial Artery Calcification ◽

Medial Artery

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Tissue-Nonspecific Alkaline Phosphatase—A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease

Biomolecules ◽

10.3390/biom10121648 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1648

Author(s):

Daniel Liedtke ◽

Christine Hofmann ◽

Franz Jakob ◽

Eva Klopocki ◽

Stephanie Graser

Keyword(s):

Alkaline Phosphatase ◽

Clinical Symptoms ◽

Current Knowledge ◽

Systemic Disease ◽

Loss Of Function ◽

Inorganic Pyrophosphate ◽

Wide Range ◽

Mineralization Processes ◽

Tissue Nonspecific Alkaline Phosphatase

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme’s role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.

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Pathophysiology of vascular calcification: Pivotal role of cellular senescence in vascular smooth muscle cells

Experimental Gerontology ◽

10.1016/j.exger.2010.07.005 ◽

2010 ◽

Vol 45 (11) ◽

pp. 819-824 ◽

Cited By ~ 64

Author(s):

D.G.A. Burton ◽

H. Matsubara ◽

K. Ikeda

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Calcification ◽

Vascular Smooth Muscle Cells ◽

Cellular Senescence ◽

Muscle Cells ◽

Pivotal Role

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Role of SGK1 in the Osteogenic Transdifferentiation and Calcification of Vascular Smooth Muscle Cells Promoted by Hyperglycemic Conditions

International Journal of Molecular Sciences ◽

10.3390/ijms21197207 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7207

Author(s):

Florian Poetsch ◽

Laura A. Henze ◽

Misael Estepa ◽

Barbara Moser ◽

Burkert Pieske ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Calcification ◽

Vascular Smooth Muscle Cells ◽

High Glucose ◽

Muscle Cells ◽

Additional Treatment ◽

Osteogenic Signaling

In diabetes mellitus, hyperglycemia promotes the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) to enhance medial vascular calcification, a common complication strongly associated with cardiovascular disease and mortality. The mechanisms involved are, however, still poorly understood. Therefore, the present study explored the potential role of serum- and glucocorticoid-inducible kinase 1 (SGK1) during vascular calcification promoted by hyperglycemic conditions. Exposure to high-glucose conditions up-regulated the SGK1 expression in primary human aortic VSMCs. High glucose increased osteogenic marker expression and activity and, thus, promoted the osteogenic transdifferentiation of VSMCs, effects significantly suppressed by additional treatment with the SGK1 inhibitor EMD638683. Moreover, high glucose augmented the mineralization of VSMCs in the presence of calcification medium, effects again significantly reduced by SGK1 inhibition. Similarly, SGK1 knockdown blunted the high glucose-induced osteogenic transdifferentiation of VSMCs. The osteoinductive signaling promoted by high glucose required SGK1-dependent NF-κB activation. In addition, advanced glycation end products (AGEs) increased the SGK1 expression in VSMCs, and SGK1 inhibition was able to interfere with AGEs-induced osteogenic signaling. In conclusion, SGK1 is up-regulated and mediates, at least partly, the osteogenic transdifferentiation and calcification of VSMCs during hyperglycemic conditions. Thus, SGK1 inhibition may reduce the development of vascular calcification promoted by hyperglycemia in diabetes.

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