Decreased heart rate variability (HRV) is a major risk factor for sudden death and cardiovascular disease. We previously demonstrated that parasympathetic dysfunction in the heart of Akita type I diabetic mice was due to a decrease in the level of the Sterol Response Element Binding-Protein (SREBP-1). Here we demonstrate that hyperactivity of GSK3β in the atrium of the Akita mouse results in decreased SREBP-1, attenuation of parasympathetic modulation of heart rate, measured as a decrease in the high frequency (HF) fraction of HRV in the presence of propranolol, and a decrease in expression of the GIRK4 subunit of IKAch, the ion channel which mediates the heart rate response to parasympathetic stimulation. Treatment of atrial myocytes with the GSK3β inhibitor Kenpaullone increased levels of SREBP-1 and expression of GIRK4 and IKAch, while a dominant active-GSK3β mutant decreased SREBP-1 and GIRK4 expression. In Akita mice treated with GSK3β inhibitors Li+ and/or CHIR-99021, Li+ increased IKAch, and both Li+ and CHIR-99021 partially reversed the decrease in HF fraction while increasing GIRK4 and SREBP-1 expression. These data support the conclusion that increased GSK3β activity in the type I diabetic heart plays a critical role in parasympathetic dysfunction via an effect on SREBP-1, supporting GSK3β as a new therapeutic target for Diabetic Autonomic Neuropathy.
- Received October 24, 2013.
- Accepted January 13, 2014.
- © 2014 by the American Diabetes Association.
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