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

J Bone Miner Res. 2015 May;30(5):824-36. doi: 10.1002/jbmr.2420.

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.

Keywords: GENETIC ANIMAL MODELS; MATRIX MINERALIZATION; PRECLINICAL STUDIES; THERAPEUTICS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase / antagonists & inhibitors
  • Alkaline Phosphatase / metabolism*
  • Animals
  • Animals, Newborn
  • Aorta / enzymology
  • Aorta / pathology
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Male
  • Mice, Transgenic
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / enzymology*
  • Muscle, Smooth, Vascular / physiopathology*
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Treatment Outcome
  • Ultrasonography
  • Vascular Calcification / blood
  • Vascular Calcification / diagnostic imaging
  • Vascular Calcification / enzymology*
  • Vascular Calcification / physiopathology*

Substances

  • Enzyme Inhibitors
  • RNA, Messenger
  • Alkaline Phosphatase
  • alkaline phosphatase 2, mouse