Dysregulation of FOXO1 (Forkhead Box O1 Protein) Drives Calcification in Arterial Calcification due to Deficiency of CD73 and Is Present in Peripheral Artery Disease

Author:

Moorhead William J.12,Chu Claire C.12,Cuevas Rolando A.12,Callahan Jack12,Wong Ryan12,Regan Cailyn12,Boufford Camille K.12,Sur Swastika12,Liu Mingjun12,Gomez Delphine12,MacTaggart Jason N.3,Kamenskiy Alexey4,Boehm Manfred5,St. Hilaire Cynthia126ORCID

Affiliation:

1. From the Department of Medicine, Division of Cardiology, University of Pittsburgh, PA (W.J.M., C.C.C., R.A.C., J.C., R.W., C.R., C.K.B., S.S., M.L., D.G., C.S.H.)

2. Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, PA (W.J.M., C.C.C., R.A.C., J.C., R.W., C.R., C.K.B., S.S., M.L., D.G., C.S.H.)

3. Department of Surgery, University of Nebraska Medical Center, Omaha (J.N.M.)

4. Department of Biomechanics, University of Nebraska Omaha (A.K.)

5. Laboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, MD (M.B.).

6. Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, PA (C.S.H.)

Abstract

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 increased ALPL expression 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 human ALPL promoter. 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 reduced ALPL expression and TNAP activity and prevented calcification. Mutating the FOXO1 binding site reduced ALPL promoter 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 human ALPL gene via a FOXO1-dependent mechanism. Decreased CD73 and increased FOXO1 was also observed in more common peripheral artery disease calcification.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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