P178Cardiac expression and activation of NF-kB in association with enhanced spleen inflammation in mice with obesity and diabetes

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Abstract

Inflammation serves as a risk factor for atherosclerosis. In diabetes, abnormal production of inflammatory factors contribute to cardiovascular dysfunction. The nuclear factor NF-kB plays an important role in inflammatory signal transduction.

Objective

To test the association of spleen inflammatory responses and activation of CD1d-restricted NKT cells, with expression and activation of NF-kB in the hearts of obese hyperinsulinemic diabetic mice.

Objective

Db/db and CD1d-knockout mice of both genders, in comparison with their respective background wild-type C57BL/6 and Balb/C were examined. The spleen tissues of db/db mice displayed increased mRNA levels of TNF-α and TNF-α receptor type 1, and higher ratio of CD1 + NK-T cells vs. CD3 + cells compared with controls. In the heart of db/db mice, although no obvious infiltration of inflammatory cells was found, mRNA levels of TNF-α receptor type 1, NF-kB DNA-binding activity, nuclear expression of p65 and activation of p52 subunit were significantly higher compared with controls. Histological examinations showed marked accumulation of lipid droplets within cardiac myocytes, but no hypertrophy or increased deposition of collagen between myocytes in db/db compared with controls. On echocardiography, the ratio of E to A transmitral flow velocities (an indicator of diastolic function) was significantly decreased in db/db mice, while indexes of systolic function were marginally affected. These changes were paralleled by increased mRNA expression of brain natriuretic peptide.

Conclusions

These results provide evidence for the presence of NF-kB activation and diastolic dysfunction in the heart of db/db mice. The abnormal immune responses and TNF-α production in the spleen tissue can contribute to NF-kB activation and cardiac dysfunction in type 2 diabetes.

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