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Pathophysiological Role of Vascular Smooth Muscle Alkaline Phosphatase in Medial Artery Calcification
Author(s) -
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
Publication year - 2015
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.2420
Subject(s) - vascular smooth muscle , calcification , endocrinology , downregulation and upregulation , medicine , alkaline phosphatase , muscle hypertrophy , osteoblast , pathology , biology , biochemistry , smooth muscle , in vitro , gene , enzyme
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. © 2015 American Society for Bone and Mineral Research.