Abstract 161: Visceral Obesity and Calcific Aortic Valve Disease Is Mediated by S100/Calgranulin
Purpose: Circulating serum levels of human S100/calgranulins have been associated with diabetes, coronary artery disease and increased cardiovascular mortality in clinical studies. To test whether S100/calgranulins are biomarker of inflammation or directly mediate disease, we exploited the fact that mice lack the gene for S100A12, and generated a novel humanized mouse with transgenic expression of human S100/calgrnaulin.
Methods: hBAC-S100 mice were generated in C57BL6/J mice by expression of a bacterial artificial chromosome of the human S100/calgranulin gene cluster containing genes and regulatory elements for S100A8/9 and S100A12 (60kb). F3 animals and wild type (WT) control littermate mice were maintained in pathogen free barrier facility with free access to water and regular rodent chow diet and studied at age 1, 3 and 12 months.
Results: S100A12 protein is expressed in myeloid circulating blood cells and present in the serum of hBAC-S100 mice (25 ng/ml serum), but was not detected in WT mice. BAC-S100 mice developed normal and showed marked increase in visceral adiposity at 12 months upon DEXA scanning (25% vs 12%, p<0.05). Gene expression in white adipose tissue (WAT) of lean hBAC-S100 age 4 weeks was increased for T- and B cell marker and unchanged for F4/80, CD68, and MCP-1 compared to age and gender matched WT littermate. In 12M old mice, WAT showed increased F4/80, CD68 and MCp-1(mRNA and immunohistochemistry) and no difference in T-and B cell markers. Adiposity in 12M old hBAC-S100 mice was associated with hyperinsulinemia and impaired oral glucose tolerance test and no evidence of hepatic steatosis. Elevated serum interleukin-6 and reduced levels of adiponectin preceeded development of adiposity and was present in young hBAC-S100 mice. Alizarin Red stained serial sections revealed calcification nodules (50-100μm in size) on the aortic valve leafleat and few osteoblast-like cells in the ascending aortic media in all 12-months old hBAC-S100A12 and very scant to absent calcification in control litter mate mice (n=6, p<0.005). In vivo ECHO showed abnormal mitral valve doppler flow with reduced ratio of early (E) to atrial (A) filling (E/A ratio 0.85 and 1.22, p=0.03) indicative of diastolic dysfunction. Left ventricular systolic function, size, and aortic valve gradients were not different between hBAC-S100 and WT mice.
Conclusion: Circulating myeloid derived human S100/calgranulin is sufficient to induce a sustained inflammatory state and is associated with the development of adiposity, hyperinsulinemia, impaired glucose tolerance and aortic valve calcification in chow fed C57BL6 mice.
- © 2012 by American Heart Association, Inc.