ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the generation of AMP.

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: Yvonne Nitschke, Yan Yan, Insa Buers, Kristina Kintziger, Kim Askew, Frank Rutsch
• Journal: Experimental & molecular medicine (Exp Mol Med) Vol. 50 Issue 10 Pg. 1-12 (10 29 2018) ISSN: 2092-6413 [Electronic] United States
• PMID: 30369595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunoglobulin Fc Fragments
• RNA, Small Interfering
• Recombinant Fusion Proteins
• Adenosine Monophosphate
• Adenosine Triphosphate
• Phosphoric Diester Hydrolases
• ectonucleotide pyrophosphatase phosphodiesterase 1
• Pyrophosphatases

Topics

• Adenosine Monophosphate (biosynthesis)
• Adenosine Triphosphate (blood, metabolism)
• Animals
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Female
• Gene Knockout Techniques
• Humans
• Immunoglobulin Fc Fragments (genetics, pharmacology)
• Induced Pluripotent Stem Cells (cytology, metabolism)
• Male
• Mice
• Mice, Knockout
• Models, Biological
• Myocytes, Smooth Muscle (cytology, metabolism)
• Neointima (etiology, metabolism, pathology, prevention & control)
• Phosphoric Diester Hydrolases (genetics, pharmacology)
• Pyrophosphatases (genetics, pharmacology)
• RNA, Small Interfering (genetics)
• Rats
• Recombinant Fusion Proteins (genetics, pharmacology)
• Vascular Calcification (drug therapy, etiology, metabolism, pathology)