ATP-based Therapy Prevents Vascular Calcification and Extends Longevity in a Mouse Model of Hutchinson–Gilford Progeria Syndrome

Significance Hutchinson–Gilford progeria syndrome (HGPS) is an extremely rare sporadic genetic disorder in children characterized by premature aging and accelerated cardiovascular disease, including vascular calcification. The molecular mechanism leading to vascular calcification in HGPS was analyzed in a mouse model of progeria, which showed a profound deficiency in extracellular pyrophosphate, a potent inhibitor of vascular calcification. This study showed that a treatment strategy focused on improving extracellular pyrophosphate metabolism could constitute an alternative therapy against this devastating syndrome and other diseases with pyrophosphate deficiency. Pyrophosphate deficiency may explain the excessive vascular calcification found in children with Hutchinson–Gilford progeria syndrome (HGPS) and in a mouse model of this disease. The present study found that hydrolysis products of ATP resulted in a <9% yield of pyrophosphate in wild-type blood and aortas, showing that eNTPD activity (ATP → phosphate) was greater than eNPP activity (ATP → pyrophosphate). Moreover, pyrophosphate synthesis from ATP was reduced and pyrophosphate hydrolysis (via TNAP; pyrophosphate → phosphate) was increased in both aortas and blood obtained from mice with HGPS. The reduced production of pyrophosphate, together with the reduction in plasma ATP, resulted in marked reduction of plasma pyrophosphate. The combination of TNAP inhibitor levamisole and eNTPD inhibitor ARL67156 increased the synthesis and reduced the degradation of pyrophosphate in aortas and blood ex vivo, suggesting that these combined inhibitors could represent a therapeutic approach for this devastating progeroid syndrome. Treatment with ATP prevented vascular calcification in HGPS mice but did not extend longevity. By contrast, combined treatment with ATP, levamisole, and ARL67156 prevented vascular calcification and extended longevity by 12% in HGPS mice. These findings suggest a therapeutic approach for children with HGPS.