P312Aortic valve calcification is induced by transgenic expression of pro-inflammatory human S100A12

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Abstract

Purpose

Circulating serum levels of human S100A12 have been associated with diabetes, coronary artery disease and increased cardiovascular mortality. To test whether S100A12 is a biomarker or directly mediates vascular disease, we exploited the fact that mice lack the gene for S100A12, and created a novel transgenic mouse expressing human S100A12.

Methods

hBAC-S100 mice on C57BL6/J strain was generated using a bacterial artificial chromosome of the human S100/calgranulin gene cluster containing S100A8/9 and S100A12 with regulatory elements. This approach ensures human protein expression in the mouse similar to the expression pattern in humans, i.e. no specific tissue promoter was utilized. hBAC-S100 and wild type (WT) control litter mate mice were housed with free access to water and regular rodent chow diet and studied at age 3 and 12 months.

Results

S100A12 protein is expressed in myeloid circulating blood cells and present in the serum of hBAC-S100 mice (25-75 ng/ml serum), but was not detected in WT. hBAC-S100 mice developed normal with equal weight at 3 months and increased weight (31.3 g vs 24.2 g, p < 0.001) and abdominal adiposity (1.56g vs.0.25g, p < 0.001) at 12months in female and male mice. There was no difference in glucose tolerance test, insulin tolerance test and serum cholesterol, although serum insulin was significantly elevated in 3 months- and 12 months old hBAC. Serum interleukin-6 was elevated at 3-months of age (44 ng/ml vs. 18 ng/ml, p=0.02) and in 12-months old hBAC-S100 (137ng/ml vs 61 ng/ml, p=0.03). Alizarin Red stained serial sections of the aortic valve revealed many micro-calcification spots (10-50 um) in all aged hBAC-S100A12, and very scant to absent calcification in control litter mate mice (n=6, p < 0.005). The calcification co-localize to osteoblast like cells, without overt infiltration of inflammatory cells or necrosis upon hematoxylin & eosin stained serial sections. 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 with elevated serum interleukin-6 and serum insulin, and is associated with the development of visceral adiposity and development of aortic valve sclerosis in normolipidemic adult mice. We currently investigate mechanisms of S100/calgranulin induced aortic valve calcification.

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