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

• Type of Material: Article
• Authors: Campbell R. Sheen, Sanford Burnham Medical Research Institute; Pia Kuss, Sanford Burnham Medical Research Institute; Sonoko Narisawa, Sanford Burnham Medical Research Institute; Manisha C. Yadav, Sanford Burnham Medical Research Institute; Jessica Nigro, Sanford Burnham Medical Research Institute; Wei Wang, Sanford Burnham Medical Research Institute; T. Nicole Chhea, Sanford Burnham Medical Research Institute; Eduard A. Sergienko, Sanford Burnham Medical Research Institute; Kapil Kapoor, Sanford Burnham Medical Research Institute; Michael R. Jackson, Sanford Burnham Medical Research Institute; Marc F. Hoylaerts, University of Leuven; Anthony B. Pinkerton, Sanford Burnham Medical Research Institute; W Charles O'Neill, Emory University; Jose Luis Millan, Sanford Burnham Medical Research Institute
• Language: English
• Date: 2015-05-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 American Society for Bone and Mineral Research. © 2014 American Society for Bone and Mineral Research.
• Final Published Version (URL): http://dx.doi.org/10.1002/jbmr.2420
• Title of Journal or Parent Work: Journal of Bone and Mineral Research
• ISSN: 0884-0431
• Volume: 30
• Issue: 5
• Start Page: 824
• End Page: 836
• Grant/Funding Information: This work was supported in part by grants X01MH077602, RC1HL101899, DE012889 and AG045933 from the National Institutes of Health, USA.; CRS is the recipient of an American Heart Association Postdoctoral Fellowship.; PK is the recipient of a Research Fellowship from the German Research Foundation (DFG).
• Keywords: Life Sciences & Biomedicine; Science & Technology; INFANTILE HYPOPHOSPHATASIA; ENZYME-REPLACEMENT THERAPY; BONE; PRECLINICAL STUDIES; MINERALIZATION; PLASMA; GENES; Endocrinology & Metabolism; GENETIC ANIMAL MODELS; CELL MEMBRANE GLYCOPROTEIN-1; MATRIX MINERALIZATION; EXTRACELLULAR PYROPHOSPHATE METABOLISM; THERAPEUTICS; INORGANIC PYROPHOSPHATE; AORTIC CALCIFICATION
• Research Categories: Biology, Genetics; Health Sciences, Medicine and Surgery

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.