Abstract 146: Phosphodiesterase 10A Mediates Arterial Calcification Through A P38/MAPK-MMP3 Signaling

Abstract

Background: Vascular calcification is prevalent in patients with atherosclerosis, chronic kidney disease (CKD), diabetes, and peripheral artery disease (PAD). When located in the arterial media, it is strongly associated with increased cardiovascular morbidity and mortality. The cyclic nucleotides cAMP and cGMP play important regulatory roles in a variety of human diseases that are controlled by distinct phosphodiesterase (PDE) isozymes. We have recently found that PDE10A is the most highly induced isoform in a rodent model of arterial calcification. The function and underlying mechanisms of PDE10A in medial artery calcification, however, remain unknown. Methods: Vascular smooth muscle cell (VSMC) calcification was mediated by a high phosphate media. Medial artery calcification was induced by vitamin D 3 injection and 5/6 nephrectomy calcification models. Vascular calcification was assessed by calcium assay and Von Kossa staining. Results: PDE10A was markedly increased in calcifying VSMCs in vitro , calcified arteries in vivo , and calcified human tibial arteries from patients with PAD. Knockdown or inhibition of PDE10A markedly attenuated phosphate-induced VSMC osteogenic transformation and calcification in VSMCs. Conversely, overexpression of PDE10A increased VSMC calcification. Deficiency and inhibition of PDE10A significantly decreased arterial calcification in vivo . Several labs including our own have demonstrated that matrix metallopeptidases (MMPs) are involved in vascular calcification. Using bioinformatics analysis and loss-of-function strategy, we found that MMP-3 could be regulated by PDE10A in calcifying VSMCs. Our further mechanistic studies showed that knockdown or inhibition of PDE10A decreased activated p38 MAPK and that inhibition of p38 MAPK attenuated MMP-3 upregulation under a calcifying condition. These data suggest that PDE10A mediates arterial calcification through a p38 MAPK-MMP-3 signaling pathway. Conclusion: PDE10A is a key regulator in the development of medial artery calcification. Our findings provide insight into the use of PDE10A inhibition strategies to reduce arterial calcification in patients with CKD and PAD.