Abstract 279: Role of PDE10A in Arterial Calcification

Abstract

Vascular calcification is highly prevalent in patients with diabetes mellitus and chronic kidney disease. When located in the media, arterial calcification is strongly associated with increased cardiovascular morbidity and mortality. The second messenger cyclic nucleotides cAMP and cGMP, controlled by distinct cyclic nucleotide phosphodiesterase (PDE) isozymes, play important regulatory roles in a variety of human diseases. Using a qPCR PDE array, we found that PDE10A was the most highly induced among all PDE genes in a rat model of medial artery calcification. PDE10A expression was markedly increased in calcified arteries from rats with chronic kidney disease and in tibial arteries from patients with peripheral artery disease. Interestingly, it co-localized with osteogenic markers in these specimens. In vitro , PDE10A knockdown using siRNA, and inhibition with a synthetic inhibitor markedly reduced osteogenic transformation and calcification of vascular SMC exposed to high phosphate levels. Aortic rings from PDE10A knockout mice showed significantly less Pi-induced medial calcification than those from wild-type controls. Deficiency of PDE10A also reduced medial calcification in a mouse medial calcification model in vivo . Mechanistic studies to elucidate the signaling alterations invoked by PDE10A are ongoing. These findings suggest that PDE10A plays a crucial role in the development of medial artery calcification, and that targeting it may provide a novel therapeutic strategy for reducing medial calcification and improving outcomes in patients with PAD.