期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 40, 期 7, 页码 1680-1694出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.119.313765
关键词
alkaline phosphatase; arteries; calcification; lower extremity
资金
- National Heart, Lung, and Blood Institute [K22 HL117917]
- Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute
- University of Pittsburgh School of Medicine Division of Cardiology
- National Heart, Lung, And Blood Institute of the National Institutes of Health [HL125736, HL147128]
Objective: The recessive disease arterial calcification due to deficiency of CD73 (ACDC) presents with extensive nonatherosclerotic medial layer calcification in lower extremity arteries. Lack of CD73 induces a concomitant increase in TNAP (tissue nonspecific alkaline phosphatase;ALPL), a key enzyme in ectopic mineralization. Our aim was to investigate how loss of CD73 activity leads to increasedALPLexpression and calcification in CD73-deficient patients and assess whether this mechanism may apply to peripheral artery disease calcification. Approach and Results: We previously developed a patient-specific disease model using ACDC primary dermal fibroblasts that recapitulates the calcification phenotype in vitro. We found that lack of CD73-mediated adenosine signaling reduced cAMP production and resulted in increased activation of AKT. The AKT/mTOR (mammalian target of rapamycin) axis blocks autophagy and inducing autophagy prevented calcification; however, we did not observe autophagy defects in ACDC cells. In silico analysis identified a putative FOXO1 (forkhead box O1 protein) binding site in the humanALPLpromoter. Exogenous AMP induced FOXO1 nuclear localization in ACDC but not in control cells, and this was prevented with a cAMP analogue or activation of A2a/2b adenosine receptors. Inhibiting FOXO1 reducedALPLexpression and TNAP activity and prevented calcification. Mutating the FOXO1 binding site reducedALPLpromoter activation. Importantly, we provide evidence that non-ACDC calcified femoropopliteal arteries exhibit decreased CD73 and increased FOXO1 levels compared with control arteries. Conclusions: These data show that lack of CD73-mediated cAMP signaling promotes expression of the humanALPLgene via a FOXO1-dependent mechanism. Decreased CD73 and increased FOXO1 was also observed in more common peripheral artery disease calcification.
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