Abstract 291: Phosphodiesterase 10A Regulates Medial Artery Calcification
| Autor: | Yujun Cai, Yangzhouyun Xie, Alexa Berezowitz, Alyssa M Flores, Xue-Lin Wang, Raul J Guzman |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 42 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Vascular calcification results from deposition of calcium hydroxyapatite crystals in the vessel wall. It is highly prevalent in patients with chronic kidney disease (CKD), diabetes, and peripheral artery disease (PAD). In lower extremity arteries, elevated calcification levels are associated with an increased risk of ischemic events including amputation. The 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 isoform in a rodent model of arterial calcification. PDE10A was also markedly increased in calcifying vascular smooth muscle cells (VSMCs) in vitro , calcified arteries from rodents with CKD, and calcified human tibial arteries. Knockdown or inhibition of PDE10A markedly attenuated high phosphate-induced VSMC osteogenic transformation and calcification in both rat and human VSMCs. Importantly, deficiency of PDE10A significantly decreased arterial calcification in both ex vivo aortic ring and in vivo vitamin D 3 medial calcification models. Several labs including our own have previously demonstrated that matrix metallopeptidases (MMPs) are involved in vascular calcification. Using a loss-of-function strategy and bioinformatics analysis, we found that MMP-3 expression was regulated by PDE10A in calcifying VSMCs. Our further mechanistic studies showed that PDE10A could regulate vascular calcification by controlling p38 MAPK signaling and MMP-3 activity through cGMP/PKG signaling. These findings suggest that PDE10A plays a critical role in the development of medial artery calcification, and that targeting it may provide a novel therapeutic strategy to reduce medial calcification in patients with PAD and CKD with the ultimate goal of preventing major limb amputation. |
| Databáze: | OpenAIRE |
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