title: 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.
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Campbell R
authors.initials: CR
authors.lastname: Sheen
authors.forename: Pia
authors.initials: P
authors.lastname: Kuss
authors.forename: Sonoko
authors.initials: S
authors.lastname: Narisawa
authors.forename: Manisha C
authors.initials: MC
authors.lastname: Yadav
authors.forename: Jessica
authors.initials: J
authors.lastname: Nigro
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: T Nicole
authors.initials: TN
authors.lastname: Chhea
authors.forename: Eduard A
authors.initials: EA
authors.lastname: Sergienko
authors.forename: Kapil
authors.initials: K
authors.lastname: Kapoor
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jackson
authors.forename: Marc F
authors.initials: MF
authors.lastname: Hoylaerts
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Pinkerton
authors.forename: W Charles
authors.initials: WC
authors.lastname: O'Neill
authors.forename: José Luis
authors.initials: JL
authors.lastname: Millán
mesh_terms: D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001011:Aorta / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D014463:Ultrasonography; D061205:Vascular Calcification / Q000097:blood / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000503:physiopathology*
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; C510878:ALPL protein, mouse; D000469:Alkaline Phosphatase
keywords: GENETIC ANIMAL MODELS; MATRIX MINERALIZATION; PRECLINICAL STUDIES; THERAPEUTICS