PDF(Pubmed)
Abstract：
The Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) ectoenzyme regulates vascular intimal proliferation and mineralization of bone and soft tissues. ENPP1 variants cause Generalized Arterial Calcification of Infancy (GACI), a rare genetic disorder characterized by ectopic calcification, intimal proliferation, and stenosis of large- and medium-sized arteries. ENPP1 hydrolyzes extracellular ATP to pyrophosphate (PPi) and AMP. AMP is the precursor of adenosine, which has been implicated in the control of neointimal formation. Herein, we demonstrate that an ENPP1-Fc recombinant therapeutic inhibits proliferation of vascular smooth muscle cells (VSMCs) in vitro and in vivo. Addition of ENPP1 and ATP to cultured VSMCs generated AMP, which was metabolized to adenosine. It also significantly decreased cell proliferation. AMP or adenosine alone inhibited VSMC growth. Inhibition of ecto-5\'-nucleotidase CD73 decreased adenosine accumulation and suppressed the anti-proliferative effects of ENPP1/ATP. Addition of AMP increased cAMP synthesis and phosphorylation of VASP at Ser157. This AMP-mediated cAMP increase was abrogated by CD73 inhibitors or by A2aR and A2bR antagonists. Ligation of the carotid artery promoted neointimal hyperplasia in wild-type mice, which was exacerbated in ENPP1-deficient ttw/ttw mice. Prophylactic or therapeutic treatments with ENPP1 significantly reduced intimal hyperplasia not only in ttw/ttw but also in wild-type mice. These findings provide the first insight into the mechanism of the anti-proliferative effect of ENPP1 and broaden its potential therapeutic applications beyond enzyme replacement therapy.
摘要：
三核苷酸焦磷酸酶/磷酸二酯酶1（ENPP1）胞外酶调节血管内膜增殖和骨和软组织的矿化。ENPP1变异导致婴儿动脉钙化(GACI),一种以异位钙化为特征的罕见遗传病，内膜增生,和大中型动脉狭窄。ENPP1将胞外ATP水解为焦磷酸(PPi)和AMP。AMP是腺苷的前体,这与新内膜形成的控制有关。在这里，我们证明了ENPP1-Fc重组治疗剂在体外和体内抑制血管平滑肌细胞(VSMC)的增殖。将ENPP1和ATP添加到培养的VSMC中产生AMP，代谢成腺苷.它还显著降低细胞增殖。AMP或腺苷单独抑制VSMC生长。抑制ecto-5'-核苷酸酶CD73减少腺苷积累并抑制ENPP1/ATP的抗增殖作用。AMP的添加增加了Ser157处的cAMP合成和VASP的磷酸化。CD73抑制剂或A2aR和A2bR拮抗剂消除了AMP介导的cAMP增加。颈动脉结扎促进野生型小鼠的新生内膜增生,在ENPP1缺陷型ttw/ttw小鼠中加剧。使用ENPP1的预防性或治疗性治疗不仅在ttw/ttw中而且在野生型小鼠中显著减少了内膜增生。这些发现为ENPP1的抗增殖作用机制提供了首次见解，并将其潜在的治疗应用扩展到酶替代疗法之外。
