Smooth Muscle Cell-Specific Expression of Cyclic Nucleotide Phosphodiesterase 10a Promotes the Development of Medial Artery Calcification.

KEY POINTS: Phosphodiesterase 10A (PDE10A) expression was upregulated in calcified arteries from patients and animal models. Genetic deficiency of PDE10A attenuated medial artery calcification and osteogenic transformation of smooth muscle cells. Pharmacological inhibition of PDE10A reduced medial artery calcification in CKD models.

BACKGROUND

Medial artery calcification is highly prevalent in patients with CKD and peripheral artery disease. It is strongly associated with higher cardiovascular morbidity and mortality. The second messenger cyclic nucleotides cAMP and cyclic guanosine monophosphate play important regulatory roles in a variety of human diseases, which are controlled by distinct phosphodiesterase isozymes. Phosphodiesterases have proven to be highly effective drug targets for the treatment of various conditions. Their function and regulation in medial artery calcification, however, remain unknown.

METHODS

To investigate the role of phosphodiesterase 10A (PDE10A) in medial artery calcification, we used calcified human tibial arteries from patients with peripheral artery disease, calcified arteries from in vivo models, and calcifying vascular smooth muscle cells in vitro . Functional studies were conducted using PDE10A knockdown, overexpression, global deletion, and smooth muscle cell-specific deficiency models. Furthermore, we used an ex vivo aortic ring culture model. The therapeutic potential of the pharmacological PDE10A inhibitor, TAK-063, was evaluated in two distinct in vivo calcification models: vitamin D 3 injection and the 5/6 nephrectomy CKD model.

RESULTS

We observed that PDE10A was increased in calcifying vascular smooth muscle cells in vitro , calcified arteries in vivo , and calcified human tibial arteries. Knockdown and inhibition of PDE10A markedly attenuated phosphate-induced smooth muscle cell osteogenic transformation and calcification, whereas overexpression of PDE10A enhanced smooth muscle cell calcification. Consistently, both global and smooth muscle cell-specific PDE10A deficiency significantly reduced medial artery calcification in vivo , and deletion of PDE10A alleviated calcification in the aortic ring model. Mechanistically, PDE10A promoted medial artery calcification through activation of the p38 mitogen-activated protein kinase-matrix metalloproteinase-3 signaling axis. In addition, the inhibitor TAK-063 significantly reduced medial artery calcification in both the vitamin D 3 and 5/6 nephrectomy models.

CONCLUSIONS

PDE10A was a critical mediator of medial artery calcification, and pharmacological inhibition effectively reduced medial artery calcification in vivo .