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ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the generation of AMP.
Exp Mol Med. 2018 10 29; 50(10):1-12.EM

Abstract

Generalized arterial calcification of infancy (GACI) is associated with widespread arterial calcification and stenoses and is caused by mutations in ENPP1. ENPP1 encodes for ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which cleaves ATP to generate inorganic pyrophosphate (PPi) and adenosine monophosphate (AMP) extracellularly. The current study was designed to define the prevalence of arterial stenoses in GACI individuals and to identify the mechanism through which ENPP1 deficiency causes intimal proliferation. Furthermore, we aimed to effectively prevent and treat neointima formation in an animal model of GACI through the systemic administration of recombinant human (rh)ENPP1-Fc protein. Based on a literature review, we report that arterial stenoses are present in at least 72.4% of GACI cases. We evaluated the effect of rhENPP1-Fc on ENPP1-silenced human vascular smooth muscle cells (VSMCs) and on induced intimal proliferation in Enpp1-deficient ttw/ttw mice treated with carotid ligation. We demonstrate that silencing ENPP1 in VSMCs resulted in a tenfold increase in proliferation relative to that of cells transfected with negative control siRNA. The addition of rhENPP1-Fc, AMP or adenosine restored the silenced ENPP1-associated proliferation. In contrast, neither PPi nor etidronate, a current off-label treatment for GACI, had an effect on VSMC proliferation. Furthermore, subcutaneous rhENPP1-Fc protein replacement was effective in preventing and treating intimal hyperplasia induced by carotid ligation in an animal model of GACI. We conclude that ENPP1 inhibits neointima formation by generating AMP. RhENPP1-Fc may serve as an approach for the effective prevention and treatment of arterial stenoses in GACI.

Authors+Show Affiliations

Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Campus 1, D-48149, Münster, Germany. Cells in Motion Cluster of Excellence, Münster University, Münster, Germany.Alexion Pharmaceuticals, 100 College St, New Haven, CT, USA.Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Campus 1, D-48149, Münster, Germany. Cells in Motion Cluster of Excellence, Münster University, Münster, Germany.Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Campus 1, D-48149, Münster, Germany.Alexion Pharmaceuticals, 100 College St, New Haven, CT, USA.Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Campus 1, D-48149, Münster, Germany. frank.rutsch@ukmuenster.de. Cells in Motion Cluster of Excellence, Münster University, Münster, Germany. frank.rutsch@ukmuenster.de.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30369595

Citation

Nitschke, Yvonne, et al. "ENPP1-Fc Prevents Neointima Formation in Generalized Arterial Calcification of Infancy Through the Generation of AMP." Experimental & Molecular Medicine, vol. 50, no. 10, 2018, pp. 1-12.
Nitschke Y, Yan Y, Buers I, et al. ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the generation of AMP. Exp Mol Med. 2018;50(10):1-12.
Nitschke, Y., Yan, Y., Buers, I., Kintziger, K., Askew, K., & Rutsch, F. (2018). ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the generation of AMP. Experimental & Molecular Medicine, 50(10), 1-12. https://doi.org/10.1038/s12276-018-0163-5
Nitschke Y, et al. ENPP1-Fc Prevents Neointima Formation in Generalized Arterial Calcification of Infancy Through the Generation of AMP. Exp Mol Med. 2018 10 29;50(10):1-12. PubMed PMID: 30369595.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the generation of AMP. AU - Nitschke,Yvonne, AU - Yan,Yan, AU - Buers,Insa, AU - Kintziger,Kristina, AU - Askew,Kim, AU - Rutsch,Frank, Y1 - 2018/10/29/ PY - 2018/05/08/received PY - 2018/07/12/accepted PY - 2018/05/08/revised PY - 2018/10/30/entrez PY - 2018/10/30/pubmed PY - 2019/5/30/medline SP - 1 EP - 12 JF - Experimental & molecular medicine JO - Exp Mol Med VL - 50 IS - 10 N2 - Generalized arterial calcification of infancy (GACI) is associated with widespread arterial calcification and stenoses and is caused by mutations in ENPP1. ENPP1 encodes for ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which cleaves ATP to generate inorganic pyrophosphate (PPi) and adenosine monophosphate (AMP) extracellularly. The current study was designed to define the prevalence of arterial stenoses in GACI individuals and to identify the mechanism through which ENPP1 deficiency causes intimal proliferation. Furthermore, we aimed to effectively prevent and treat neointima formation in an animal model of GACI through the systemic administration of recombinant human (rh)ENPP1-Fc protein. Based on a literature review, we report that arterial stenoses are present in at least 72.4% of GACI cases. We evaluated the effect of rhENPP1-Fc on ENPP1-silenced human vascular smooth muscle cells (VSMCs) and on induced intimal proliferation in Enpp1-deficient ttw/ttw mice treated with carotid ligation. We demonstrate that silencing ENPP1 in VSMCs resulted in a tenfold increase in proliferation relative to that of cells transfected with negative control siRNA. The addition of rhENPP1-Fc, AMP or adenosine restored the silenced ENPP1-associated proliferation. In contrast, neither PPi nor etidronate, a current off-label treatment for GACI, had an effect on VSMC proliferation. Furthermore, subcutaneous rhENPP1-Fc protein replacement was effective in preventing and treating intimal hyperplasia induced by carotid ligation in an animal model of GACI. We conclude that ENPP1 inhibits neointima formation by generating AMP. RhENPP1-Fc may serve as an approach for the effective prevention and treatment of arterial stenoses in GACI. SN - 2092-6413 UR - https://www.unboundmedicine.com/medline/citation/30369595/ENPP1_Fc_prevents_neointima_formation_in_generalized_arterial_calcification_of_infancy_through_the_generation_of_AMP_ L2 - https://doi.org/10.1038/s12276-018-0163-5 DB - PRIME DP - Unbound Medicine ER -