Wednesday, April 2, 2025
4/2/2025
Medial Arterial Calcification in Peripheral Artery Disease - PROJECT SUMMARY Peripheral artery disease (PAD) is highly prevalent in older adults and is a comorbidity to diseases such as diabetes, chronic kidney disease, and hypertension. For decades PAD was assumed to be mainly an atherosclerotic pathology, however emerging data establish medial arterial calcification (MAC) as a distinct disease state of PAD, independent from atherosclerosis. The mechanisms driving MAC pathogenesis are unclear. We previously discovered the rare disease Arterial Calcification due to Deficiency of CD73 (ACDC), where homozygous inactivating mutations in the gene encoding the CD73 enzyme cause MAC in otherwise healthy adults. We recently found that a lack of CD73 and its product adenosine promotes FOXO1 nuclear location and FOXO1-dependent activation of the mineralizing enzyme, tissue non-specific alkaline phosphatase (ALPL/TNAP) gene promoter. Pharmacological inhibition of FOXO1 blocked TNAP activity and calcification in vitro. Importantly, we found that this CD73/FOXO1/TNAP axis was present in non-genetic common forms of MAC, indicating that CD73 is critical for peripheral vascular health. There are significant gaps in our understanding of MAC pathogenesis, and the causes and consequences of reduced CD73 and its product adenosine in this disease state. This proposal will test the central hypothesis that CD73 levels are suppressed as a consequence of activation of the DNA damage response, and that reduced CD73-mediated adenosine production alters arginine methylation to promote FOXO1-induced osteogenic gene transcription in SMCs. Aim1 will define the mechanisms by which the DNA damage response promotes vascular calcification. Aim2 will determine how reduced adenosine production alters arginine methylation and promotes the upregulation of osteogenic transcriptional programs in SMCs. We expect the completion of these complementary studies will identify a novel, druggable pathway driving MAC pathogenesis in PAD.
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