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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 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(+/-) ; Hprt(ALPL) (/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(+/-) ; Hprt(ALPL) (/-) ) 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.

SUBMITTER: Sheen CR 

PROVIDER: S-EPMC4406354 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Pathophysiological role of vascular smooth muscle alkaline phosphatase in medial artery calcification.

Sheen Campbell R CR   Kuss Pia P   Narisawa Sonoko S   Yadav Manisha C MC   Nigro Jessica J   Wang Wei W   Chhea T Nicole TN   Sergienko Eduard A EA   Kapoor Kapil K   Jackson Michael R MR   Hoylaerts Marc F MF   Pinkerton Anthony B AB   O'Neill W Charles WC   Millán José Luis JL  

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20150501 5


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  ...[more]

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