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 (PP _i) 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 PP _i 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.

Arterial disease: promising protein replacement therapy in inherited disorder

A protein replacement therapy may prove useful in tackling calcification and narrowing of the arteries in babies with a severe genetic disorder. Generalized Arterial Calcification of Infancy (GACI) is a rare condition in which infants’ arteries become calcified and their blood vessels internally scarred. It often leads to congestive heart failure. The ENPP1 gene encodes a protein that is crucial to preventing excess calcium build-up in the body. Mutations in the ENPP1 gene lead to GACI, but no therapies for the condition exist. Now, Frank Rutsch at Muenster University Children’s Hospital in Germany and co-workers have shown that administering a protein replacement can inhibit blood vessel scarring and arterial clogging in GACI mice models and in human stem cell cultures. The protein replacement boosts production of a key metabolic molecule called adenosine monophosphate.