DOI: 10.1161/circ.148.suppl_1.17022 ISSN: 0009-7322

Abstract 17022: Transcriptomic Analysis of Calciphylaxis Tissue Reveals Novel Genes Related to Vascular Calcification and Overlap With Coronary Artery Disease

Sujin Lee, Kangsan Roh, Kuldeep Singh, Wanlin Jiang, Katrina Ostrom, Claire Birchenough, Lova Kajuluri, Adam L Johnson, Scott Krinsky, Houda Bouchouari, Christian L Lino Cardenas, Matthew Eagleton, Rosalynn M Nazarian, Clint L Miller, Sagar Nigwekar, Rajeev Malhotra
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Introduction: Calciphylaxis is a rare, understudied disease of accelerated vascular calcification affecting the skin and soft tissue leading to painful wounds, amputations, and reduced survival. The underlying mechanisms of calciphylaxis remain incompletely understood.

Objective: In this study, we aimed to identify altered signaling pathways and novel differentially expressed genes (DEGs) associated with calciphylaxis and to characterize the protein expression of top DEGs in the vasculature.

Methods: 6 case and 3 control tissues were obtained from our institution’s calciphylaxis biorepository (NCT03032835). RNA sequencing analysis and pathway analysis were performed using the KEGG database. Immunofluorescent (IF) staining with co-localization analysis was performed on independent case-control samples for the top 9 upregulated DEGs. In vitro functional assessment was performed using human vascular smooth muscle cells (VSMC).

Results: 783 DEGs (FDR-adjusted p-value ≤0.05) were identified, 543 of which were upregulated (Fig 1A). 27 altered pathways enriched for calcification, thrombosis, and inflammation were identified. The top 9 upregulated DEGs (adjusted p-values ≤1.2 x10-7) were KYNU, IFI16, KCNJ15, RAB31, FNDC1, HIF1α, DEPP1, NFIL3, and TSP1. On IF, 7 of the top 9 upregulated DEGs exhibited higher protein expression compared to matched controls, some of which are highlighted in Figure 1B. These 7 genes were all upregulated in RNA sequencing analysis of human coronary arteries with atherosclerotic lesions compared to coronaries without lesions. Functional assessment of the top 3 genes in this coronary artery disease analysis (FNDC1, KYNU & KCNJ15) revealed potent effects on calcification, proliferation, and migration of VSMCs.

Conclusions: Novel genes identified in this transcriptomic study of calciphylaxis uncovered similarities with coronary artery disease and have identified previously unknown regulators of VSMC calcification.

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