SSAT – A potential novel target for the treatment of heart failure in obesity and diabetes

Abstract

Polyamines are important for cell growth and proliferation. There is no direct link between polyamine catabolism and heart disease in the current literature. Cardiac hypertrophy is the number one predictor of heart failure. It is suggested that high levels of polyamines are responsible for cardiac hypertrophy. SSAT is the rate-limiting catabolic enzyme that reduces polyamine levels in the cell. N1,N11-Diethylnorspermine (DENSPM), is a potent inducer of SSAT, and high SSAT activity may reduce the cellular polyamine concentrations. The hypothesis of this study is that SSAT may play an important role in heart failure in obesity and diabetes situations, and targeting SSAT may improve impaired heart function in those situations. Western blotting method was used to compare SSAT protein levels and liquid chromatography-mass spectrometry (LC-MS) was then used to compare the SSAT activity in three animal heart failure models, including ob/ob mouse, a model of obesity with heart failure, db/db mouse, a model of type 2 diabetes with heart failure, and streptozetozin (STZ)-injected rat, a model of type 1 diabetes with heart failure, and their control models. DENSPM treatment was applied in the obesity model and SSAT expression and activity of treated animals were compared with control animals as well. Western blotting and LC-MS results showed that SSAT expressions and activities in heart tissues of animals with heart failure were significantly lower than that in heart tissues of control animals. In obesity mouse model, obese mice treated with DENSPM had significantly higher SSAT protein and activity levels in the liver microsome, liver cytosol and heart tissues than that in controls. In conclusion, SSAT expression and activity levels in heart seem to be correlated to the heart function in obesity- or diabetic-heart failure. Treatment with DENSPM, a potent SSAT inducer, in the obesity mouse model appears to restore SSAT expression, significantly increases SSAT activity in heart tissue and improves heart function. Therefore, the enzyme SSAT may be a novel target for the treatment of heart failure in obesity and diabetes.