title: S100/Calgranulin-mediated inflammation accelerates left ventricular hypertrophy and aortic valve sclerosis in chronic kidney disease in a receptor for advanced glycation end products-dependent manner.
abstract: OBJECTIVE
  S100A12 and fibroblast growth factor 23 are biomarkers of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). We tested the hypothesis that human S100/calgranulin would accelerate cardiovascular disease in mice subjected to CKD.
  
  
  RESULTS
  A bacterial artificial chromosome of the human S100/calgranulin gene cluster containing the genes and regulatory elements for S100A8, S100A9, and S100A12 was expressed in C57BL/6J mouse (hBAC-S100) to generate a novel humanized mouse model. CKD was induced by ureteral ligation, and hBAC-S100 mice and wild-type mice were studied after 10 weeks of chronic uremia. hBAC-S100 mice with CKD showed increased fibroblast growth factor 23 in the hearts, left ventricular hypertrophy, diastolic dysfunction, focal cartilaginous metaplasia, and calcification of the mitral and aortic valve annulus together with aortic valve sclerosis. This phenotype was not observed in wild-type mice with CKD or in hBAC-S100 mice lacking the receptor for advanced glycation end products with CKD, suggesting that the inflammatory milieu mediated by S100/receptor for advanced glycation end products promotes pathological cardiac hypertrophy in CKD. In vitro, inflammatory stimuli including interleukin-6, tumor necrosis factor-α, lipopolysaccarides, or serum from hBAC-S100 mice upregulated fibroblast growth factor 23 mRNA and protein in primary murine neonatal and adult cardiac fibroblasts.
  
  
  CONCLUSIONS
  Myeloid-derived human S100/calgranulin is associated with the development of cardiac hypertrophy and ectopic cardiac calcification in a receptor for advanced glycation end products-dependent manner in a mouse model of CKD. We speculate that fibroblast growth factor 23 produced by cardiac fibroblasts in response to cytokines may act in a paracrine manner to accelerate left ventricular hypertrophy and diastolic dysfunction in hBAC-S100 mice with CKD.
authors.affiliation: From the Department of Medicine, Cardiology (L.Y., B.C., B.G., J.E., M.A.H.B.) and Medicine, Nephrology (L.M., T.S.P.), The University of Chicago, IL.
authors.forename: Ling
authors.initials: L
authors.lastname: Yan
authors.affiliation: From the Department of Medicine, Cardiology (L.Y., B.C., B.G., J.E., M.A.H.B.) and Medicine, Nephrology (L.M., T.S.P.), The University of Chicago, IL.
authors.forename: Liby
authors.initials: L
authors.lastname: Mathew
authors.affiliation: From the Department of Medicine, Cardiology (L.Y., B.C., B.G., J.E., M.A.H.B.) and Medicine, Nephrology (L.M., T.S.P.), The University of Chicago, IL.
authors.forename: Bijoy
authors.initials: B
authors.lastname: Chellan
authors.affiliation: From the Department of Medicine, Cardiology (L.Y., B.C., B.G., J.E., M.A.H.B.) and Medicine, Nephrology (L.M., T.S.P.), The University of Chicago, IL.
authors.forename: Brandon
authors.initials: B
authors.lastname: Gardner
authors.affiliation: From the Department of Medicine, Cardiology (L.Y., B.C., B.G., J.E., M.A.H.B.) and Medicine, Nephrology (L.M., T.S.P.), The University of Chicago, IL.
authors.forename: Judy
authors.initials: J
authors.lastname: Earley
authors.affiliation: From the Department of Medicine, Cardiology (L.Y., B.C., B.G., J.E., M.A.H.B.) and Medicine, Nephrology (L.M., T.S.P.), The University of Chicago, IL.
authors.forename: Tipu S
authors.initials: TS
authors.lastname: Puri
authors.affiliation: From the Department of Medicine, Cardiology (L.Y., B.C., B.G., J.E., M.A.H.B.) and Medicine, Nephrology (L.M., T.S.P.), The University of Chicago, IL. mhofmann@medicine.bsd.uchicago.edu.
authors.forename: Marion A
authors.initials: MA
authors.lastname: Hofmann Bowman
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000378:metabolism* / Q000473:pathology; D002114:Calcinosis / Q000209:etiology / Q000378:metabolism; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003971:Diastole; D004195:Disease Models, Animal; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D006349:Heart Valve Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D039841:Leukocyte L1 Antigen Complex / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D010641:Phenotype; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism; D000067616:S100A12 Protein; D012598:Sclerosis; D015398:Signal Transduction; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D018836:Inflammation Mediators; D039841:Leukocyte L1 Antigen Complex; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23
keywords: S100 proteins; glycosylation end products, advanced; hypertrophy, left ventricular; renal insufficiency, chronic