Abstract 18355: Human S100/calgranulin Accelerates Calcific Valve Disease and Promotes Cardiac Hypertrophy in Chronic Kidney Disease in a RAGE-Dependent Manner

Abstract

Purpose: Serum S100A12 and FGF 23 are biomarker for cardiovascular mortality in patients with chronic kidney disease (CKD). We test the hypothesis that S100/calgranulin accelerates cardiovascular disease in CKD. Methods: Human S100/calgranulin is expressed using a bacterial artificial chromosome containing genes and regulatory elements for S1008/9 and S100A12 (60kb) in C57BL6/J mouse (hBAC-S100). CKD was induced in hBAC-S100 mice and in wild type (WT) littermate mice by surgical ligation of the ureters. The heart and aorta were analyzed after 10 weeks of CKD. Results: S100A12 protein is expressed in myeloid cells and in serum of hBAC-S100 mice (25ng/ml serum), and increased further in response to CKD. hBAC-S100 mice with CKD developed diastolic dysfunction, ectopic cardiac calcification, hypertrophy and fibrosis measured by in-vivo echocardiography, heart weight, histology and gene expression of ANP, β-MHC, TGF-β, CTGF, and Col 1a1. Serum FGF23 was equally increased in WT/CKD and hBAC-S100/CKD compared to sham operated animals. However, intra cardiac expression of FGF23 mRNA (6 fold) and protein (2 fold) was increased only in hBAC-S100, and co-localizes to osteoblast-like cells nearby calcified fibrous tissue of the aortic and mitral valve. However, cultured cardiac fibroblasts (and VSMC) in response to calcification- inducing medium containing 10mM glycerophosphate and 10nM dexamethasone up regulate ALP, BMP-2, and MGP, but reduced FGF23 mRNA by 90%. This suggests that FGF23-positive osteoblast like cells in the heart of hBAC-S100 might stem from cells other than fibroblasts. hBAC-S100 mice lacking RAGE, the endogenous receptor for S100A12, showed attenuation of ectopic cardiac calcification, LVH, diastolic dysfunction and cardiac FGF23 expression when subjected to CKD, and the cardiac phenotype was similar to WT mice with CKD. Furthermore, aortic valve calcification develops spontaneously in 10-12-month old hBAC/S100 mice, indicating that CKD accelerates this process in hBAC/S100 mice, but is not required. Conclusion: Myeloid-derived S100/calgranulin promotes calcific valve disease in a RAGE dependent manner, possibly by selective enrichment of FGF23-positive osteoblast like cells not stemming from cardiac fibroblasts.