{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:38:04Z","timestamp":1790746684343,"version":"4.1.0"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>\n              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;\n              <jats:italic>ALPL<\/jats:italic>\n              ), a key enzyme in ectopic mineralization. Our aim was to investigate how loss of CD73 activity leads to increased\n              <jats:italic>ALPL<\/jats:italic>\n              expression and calcification in CD73-deficient patients and assess whether this mechanism may apply to peripheral artery disease calcification.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results:<\/jats:title>\n            <jats:p>\n              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\n              <jats:italic>ALPL<\/jats:italic>\n              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\n              <jats:italic>ALPL<\/jats:italic>\n              expression and TNAP activity and prevented calcification. Mutating the FOXO1 binding site reduced\n              <jats:italic>ALPL<\/jats:italic>\n              promoter activation. Importantly, we provide evidence that non-ACDC calcified femoropopliteal arteries exhibit decreased CD73 and increased FOXO1 levels compared with control arteries.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              These data show that lack of CD73-mediated cAMP signaling promotes expression of the human\n              <jats:italic>ALPL<\/jats:italic>\n              gene via a FOXO1-dependent mechanism. Decreased CD73 and increased FOXO1 was also observed in more common peripheral artery disease calcification.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.119.313765","type":"journal-article","created":{"date-parts":[[2020,5,7]],"date-time":"2020-05-07T09:00:46Z","timestamp":1588842046000},"page":"1680-1694","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":48,"title":["Dysregulation of FOXO1 (Forkhead Box O1 Protein) Drives Calcification in Arterial Calcification due to Deficiency of CD73 and Is Present in Peripheral Artery Disease"],"prefix":"10.1161","volume":"40","author":[{"suffix":"III","given":"William J.","family":"Moorhead","sequence":"first","affiliation":[{"name":"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.)"},{"name":"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.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire C.","family":"Chu","sequence":"additional","affiliation":[{"name":"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.)"},{"name":"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.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolando A.","family":"Cuevas","sequence":"additional","affiliation":[{"name":"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.)"},{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of 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