Cyclic nucleotide phosphodiesterase regulation in vascular calcification

PROJECT SUMMARY
Arterial calcification results from the deposition of calcium hydroxyapatite crystals in the vessel wall. It is highly
prevalent in patients with chronic kidney disease (CKD) and diabetes as well as those with peripheral artery
disease (PAD). When located in the arterial media, calcification is strongly associated with increased
cardiovascular morbidity and mortality. Calcification is a highly regulated process controlled by a series of
endogenous stimulators and inhibitors. Elevated phosphate levels can induce osteogenic transformation of
vascular smooth muscle cells (SMCs). These cells release extracellular matrix-degrading enzymes including
the matrix metalloproteinases (MMPs) that contribute to calcification. Despite significant progress, arterial
calcification continues to be poorly understood and no useable drugs to prevent or treat it have been developed.
For this reason, the process of identifying novel molecular targets, and developing therapies to target them are
critical for improving outcomes in our vascular patients. The second messenger cyclic nucleotides cAMP and
cGMP play important regulatory roles in a variety of human diseases that are controlled by distinct cyclic
nucleotide PDE isozymes that have proven to be ideal and feasible drug targets for the treatment of human
diseases. The function and regulation of PDEs in arterial calcification, however, remains unknown. This
proposal is based on our preliminary data showing that phosphodiesterase 1 0A (PDE10A) is the most highly
induced isoform among all PDE genes in a rodent calcification model. PDE10A is also markedly increased in
calcifying VSMCs in vitro, calcified arteries in vivo, and calcified human tibial arteries from patients with PAD.
Knockdown and inhibition of PDE10A significantly attenuate phosphate-induced VSMC osteogenic
transformation and calcification in vitro, and deficiency of PDE10A reduces arterial calcification in vivo. Using
bioinformatics analyses and a loss-of-function strategy, we have shown that the MMP family member 3 (MMP-
3, stromelysin-1) can be regulated by PDE10A in VSMCs cultured in a calcification medium. Our further
preliminary mechanistic results have shown that both knockdown and inhibition of PDE1 0A block p38 MAPK
activation in VSMCs during calcification. We have additionally found that inhibition of p38 MAPK attenuates
MMP-3 upregulation under calcifying conditions. In this project, we propose that PDE10A mediates arterial
calcification by regulating p38 MAPK-MMP-3 signaling. In this series of experiments, we will establish the role
of PDE10A in arterial calcification and provide insights into the potential use of PDE10A inhibition strategies to
reduce calcification in patients with CKD and PAD. Our aims are to 1) investigate the actions of PDE10A in
vascular SMC osteogenic transformation and arterial calcification, 2) examine the therapeutic potential of
PDE10A inhibition in arterial calcification, and 3) assess the significance of p38-MAPK-MMP-3 signaling in
PDE10A-mediated vascular calcification.

Grant Number: 5R01HL157111-04
NIH Institute/Center: NIH
Principal Investigator: Yujun Cai