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Keywords:

Science & Technology, Life Sciences & Biomedicine, Endocrinology & Metabolism, GENETIC ANIMAL MODELS, PRECLINICAL STUDIES, MATRIX MINERALIZATION, THERAPEUTICS, ENZYME-REPLACEMENT THERAPY, EXTRACELLULAR PYROPHOSPHATE METABOLISM, CELL MEMBRANE GLYCOPROTEIN-1, AORTIC CALCIFICATION, INFANTILE HYPOPHOSPHATASIA, INORGANIC PYROPHOSPHATE, BONE, PLASMA, MINERALIZATION, GENES, Alkaline Phosphatase, Animals, Animals, Newborn, Aorta, Enzyme Inhibitors, Male, Mice, Transgenic, Muscle, Smooth, Vascular, Phenotype, RNA, Messenger, Treatment Outcome, Ultrasonography, Vascular Calcification, 06 Biological Sciences, 09 Engineering, 11 Medical and Health Sciences, Anatomy & Morphology, 31 Biological sciences, 32 Biomedical and clinical sciences

Abstract:

Medial vascular calcification (MVC) is a pathological phenomenon common to a variety of conditions, including aging, chronic kidney disease, diabetes, obesity, and a variety of rare genetic diseases, that causes vascular stiffening and can lead to heart failure. 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, 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. This article is protected by copyright. All rights reserved.