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Cyclic nucleotide phosphodiesterase regulation in vascular calcification

血管钙化中环核苷酸磷酸二酯酶的调节

基本信息

批准号：
10641917
负责人：
Yujun Cai
金额：
$ 62.97万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641917
关键词：
Address Amputation Arterial Medias Arteries Attenuated Bioinformatics Blood Vessels Cardiovascular system Cell physiology Cells Chronic Kidney Failure Cyclic AMP Cyclic GMP Cyclic Nucleotides Deposition Diabetes Mellitus Drug Targeting Durapatite Enzymes Event Extracellular Matrix Extracellular Matrix Degradation Family Family member Genes Goals Human In Vitro Ischemia Isoenzymes Knockout Mice Leg Lower Extremity MAP Kinase Gene Matrix Metalloproteinases Medial Mediating Metalloproteases Morbidity - disease rate Pathologic Patients Peripheral arterial disease Pharmaceutical Preparations Physiological Play Process Protein Isoforms Rattus Regulation Risk Rodent Model Role Second Messenger Systems Series Signal Pathway Signal Transduction Smooth Muscle Myocytes Stromelysin 1 Therapeutic Tibial Arteries Time Up-Regulation Vascular Smooth Muscle Vascular calcification calcification human disease improved outcome in vivo inhibitor inorganic phosphate insight knock-down loss of function molecular targeted therapies mortality mouse model novel novel therapeutic intervention osteogenic overexpression p38 Mitogen Activated Protein Kinase phosphoric diester hydrolase prevent therapy development

项目摘要

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.

项目总结