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

ABSTRACT Medial vascular calcification (MVC) is a pathological phenomenon that causes vascular stiffening and can lead to heart failure; it is common to a variety of conditions, including aging, chronic kidney disease, diabetes, obesity, and a variety of rare genetic diseases. These conditions share...

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Published in:Journal of bone and mineral research 2015-05, Vol.30 (5), p.824-836
Main Authors: Sheen, Campbell R, Kuss, Pia, Narisawa, Sonoko, Yadav, Manisha C, Nigro, Jessica, Wang, Wei, Chhea, T Nicole, Sergienko, Eduard A, Kapoor, Kapil, Jackson, Michael R, Hoylaerts, Marc F, Pinkerton, Anthony B, O'Neill, W Charles, Millán, José Luis
Format: Article
Language:English
Subjects:
Aging
Alkaline phosphatase
Alkaline Phosphatase - antagonists & inhibitors
Alkaline Phosphatase - metabolism
Animals
Animals, Newborn
Aorta
Aorta - enzymology
Aorta - pathology
Blood pressure
Calcification
Calcification (ectopic)
Chondrocytes
Congestive heart failure
Diabetes mellitus
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Gene expression
GENETIC ANIMAL MODELS
Hypertension
Hypertrophy
Kidney diseases
Life span
Male
MATRIX MINERALIZATION
Mice, Transgenic
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - enzymology
Muscle, Smooth, Vascular - physiopathology
Pharmacokinetics
Phenotype
Phenotypes
Phosphatase
PRECLINICAL STUDIES
RNA, Messenger - genetics
RNA, Messenger - metabolism
Skeleton
Smooth muscle
THERAPEUTICS
Treatment Outcome
Ultrasonography
Vascular Calcification - blood
Vascular Calcification - diagnostic imaging
Vascular Calcification - enzymology
Vascular Calcification - physiopathology
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Summary:ABSTRACT Medial vascular calcification (MVC) is a pathological phenomenon that causes vascular stiffening and can lead to heart failure; it is common to a variety of conditions, including aging, chronic kidney disease, diabetes, obesity, and a variety of rare genetic diseases. These conditions share the common feature of tissue‐nonspecific alkaline phosphatase (TNAP) upregulation in the vasculature. To evaluate the role of TNAP in MVC, we developed a mouse model that overexpresses human TNAP in vascular smooth muscle cells in an X‐linked manner. Hemizygous overexpressor male mice (Tagln‐Cre+/–; HprtALPL/Y or TNAP‐OE) show extensive vascular calcification, high blood pressure, and cardiac hypertrophy, and have a median age of death of 44 days, whereas the cardiovascular phenotype is much less pronounced and life expectancy is longer in heterozygous (Tagln‐Cre+/–; HprtALPL/−) female TNAP‐OE mice. Gene expression analysis showed upregulation of osteoblast and chondrocyte markers and decreased expression of vascular smooth muscle markers in the aortas of TNAP‐OE mice. Through medicinal chemistry efforts, we developed inhibitors of TNAP with drug‐like pharmacokinetic characteristics. TNAP‐OE mice were treated with the prototypical TNAP inhibitor SBI‐425 or vehicle to evaluate the feasibility of TNAP inhibition in vivo. Treatment with this inhibitor significantly reduced aortic calcification and cardiac hypertrophy, and extended lifespan over vehicle‐treated controls, in the absence of secondary effects on the skeleton. This study shows that TNAP in the vasculature contributes to the pathology of MVC and that it is a druggable target. © 2015 American Society for Bone and Mineral Research.
ISSN:0884-0431
1523-4681
DOI:10.1002/jbmr.2420